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agcohn821's picture
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Hi Foldit players! Here are the Office Hours transcripts: They begin with the first one but you can find the latest one HERE

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hours 5/15- led by Beta_Helix

[10:00 AM] beta_helix: Hi everyone. I'll be here for the next hour, with the first (hopefully of many) Foldit Office Hours!
[10:01 AM] beta_helix: For anyone who doesn't know me. I'm here: http://www.cis.umassd.edu/~fkhatib/cv.html(edited)
[10:01 AM] beta_helix: and I'll be happy to chat about anything you like!
[10:02 AM] skippysk8s: hey beta helix....I think the theme of the day is hot cross buns,,,maddening to try to cover them
[10:03 AM] beta_helix: Oh yeah... those are a pain in the BUNS
[10:04 AM] beta_helix: But unfortunately, they are extremely important in design
[10:05 AM] skippysk8s: we assume so.. it is nice to see that all that work on monomer design being applied. What has surprised you about what is turning out to be useful in the last couple months
[10:07 AM] beta_helix: Honestly... it hasn't been a surprise to me. After the amazing results all of you showed the world last year with a Nature paper full of novel designs that folded up just like you predicted in the game... this is the logical next step!
[10:08 AM] beta_helix: What makes this new task harder, of course, is that we are no longer just asking you to make sure your novel design can fold on its own...
[10:10 AM] beta_helix: That is the next difficult challenge: making sure it folds up properly AND binds to the COVID-19 spike protein.
[10:10 AM] Susume2: seems like in theory we could take soem of those stable folds and fit them into the target groove
[10:11 AM] skippysk8s: is there any way we could load some of the prior proven folds into the current puzzles and try to fit them? I'm the want my Lego folder
[10:11 AM] beta_helix: That's a great point, Susume... the only main difference would be ensuring that the side facing covid can bind to the spike (as opposed to being exposed to water).
[10:12 AM] Susume2: yes, definitely need to mutate and adjust (and repeat ad nauseam)
[10:12 AM] skippysk8s: agreed-- I'm looking for less lysine and arg on at least one edge so it will fit snugly
[10:13 AM] beta_helix: That might be a series of fun puzzles, though! Everyone starts from the same Foldit Nature design, and tries to fix the binding sides
[10:13 AM] beta_helix: (I'm writing this down!)
[10:13 AM] skippysk8s: sort of like our contest... fit the block into the space
[10:14 AM] beta_helix: We always say: key in the lock!
[10:14 AM] Susume2: is it possible to evaluate shape complementarity based on just the backbone, without knowing which sidechains will be selected (well we know the ones on the virus)?
[10:15 AM] skippysk8s: does the tumbler have to be perfect? our team got some but never all of the potential bonds to meet along the edges. And can we get a filter to make the score improve the better the fit (2 questions)
[10:16 AM] beta_helix: Susume, you can get a very basic idea... but you would still want to represent the sidechains somehow, you wouldn't want to just strip them off.
[10:16 AM] Susume2: maybe make them all generic medium sized centroids
[10:16 AM] beta_helix: Many programs use centroids for example (and I know that word gives you the chills if you were around when we tried centroid mode in Foldit!)
[10:17 AM] beta_helix: exactly
[10:17 AM] Susume2: I'm just wondering if there is a way you guys could preselect a foldit design from the nature paper that will likely fit if we pick good sidechains
[10:18 AM] beta_helix: Yes, I think that would be the way to do, because some of the topologies will just fit better than others.
[10:18 AM] Susume2: auntdeen and I had lots of fun breaking centroids as a team project ;)
[10:18 AM] beta_helix: hahahahhahahahhahahaha
[10:19 AM] beta_helix: Skippysk8 for question 2, that could be possible... depending on how fast those calculations would end up being. It might just be easier to screen the folds initially on our end. But indeed, I can see how that would be a useful filter!
[10:20 AM] Susume2: as long as we know the filter takes x minutes to run, we can plan how often to apply it
[10:20 AM] skippysk8s: we were frustrated as a team with Bruno's fold... we felt like we could go for score but didn't believe the result would be useful for science
[10:21 AM] skippysk8s: many of us started trying to link those few unmet bonds, but ended up just going for score
[10:22 AM] beta_helix: Yeah, I think it would be very useful when you are trying to figure out if your topology is going to fit or if it's a waste of time. (I'll ask the team)
[10:22 AM] beta_helix: Indeed Skippysk8, I know how frustrating that is...
[10:22 AM] beta_helix: I remember the giant pi-helices from back in the day
[10:23 AM] skippysk8s: well, it can be fun lol...
[10:23 AM] beta_helix: I kept looking at those solutions and going "why are these scoring so high!?!!"
[10:23 AM] beta_helix: But that really highlights the amazing work bkoep and the rest of the Foldit Team has done with Foldit scoring in design
[10:24 AM] beta_helix: It's such an amazing journey to see the difference in high scoring monomer designs in the early days of Foldit, compared to the Nature paper.
[10:24 AM] skippysk8s: we love to game. we want to try to keep the game fun and at the same time useful
[10:25 AM] beta_helix: That is the reason for BUNS, h-bond filters, and the new filters for these coronavirus puzzles.
[10:25 AM] beta_helix: Exactly, Skippysk8... it is a fine balance, right?
[10:25 AM] skippysk8s: agreed
[10:25 AM] RockOn: It seems my PC memory usage for FoldIt is at 1,000 MB's!
[10:26 AM] beta_helix: We could make the game painful accurate (like an MD simulation with waters) but I promise you it would not be much fun!
[10:26 AM] RockOn: What has changed Windows or FoldIt
[10:26 AM] beta_helix: Rock On!
[10:26 AM] beta_helix: oh, that's a bad thing... right. My bad
[10:26 AM] RockOn: How bad?
[10:26 AM] beta_helix: It's always easy to blame Windows (and fun too!) but indeed Foldit is constantly changing.
[10:27 AM] beta_helix: Have you noticed a difference between Foldit updates?
[10:27 AM] RockOn: 33% of the CPU
[10:27 AM] Susume2: RockOn do you mean RAM footprint? or something else?
[10:27 AM] RockOn: Yes, running taskmgr
[10:28 AM] RockOn: Just 1 client and nothing else (app related)
[10:28 AM] beta_helix: Did you have this problem with previous versions of Foldit?
[10:28 AM] RockOn: No, not unless 2 clients wee running for hours
[10:29 AM] RockOn: One crash today running helix twister
[10:30 AM] skippysk8s: my old computer was at 100% with one client -- ran alternating clients with 2 open... it was about 12 years old. the biggest problem is that all the "ligand" cells count towards puzzle size, so it is getting harder with small computers
[10:30 AM] beta_helix: Hmm... I quickly scanned our feedback and don't see any other Windows reports. https://fold.it/portal/feedback Was there a recent Windows update that was installed?
[10:30 AM] skippysk8s: it couldn't do today's puzzles at all
[10:30 AM] Susume2: devprev got pushed to main about a week ago
[10:31 AM] beta_helix: Skippysk8, you mean 1838?
[10:31 AM] Susume2: I suspect one thing that pushes RAM per client up is using all the quicksave slots - some scripts use very many of them
[10:32 AM] skippysk8s: I couldn't do any of the COVID puzzle on it
[10:32 AM] skippysk8s: puzzles
[10:32 AM] beta_helix: Undo graph as well, right Susume?
[10:32 AM] Susume2: yes probably
[10:34 AM] Susume2: changing tracks and changing back should free the undo graph memory, idk that frees the quicksave slots as well (have not tried it)
[10:34 AM] RockOn: I see the graph at 100 for length AND Memory Usage is at 100%
[10:34 AM] beta_helix: I'll bring these issues up to the rest of the team...
[10:35 AM] skippysk8s: I live at 25 undos RockOn.. not ideal. I just save before I start a new recipe each time
[10:36 AM] RockOn: I set Memory Usage to 25% and Taskmgr shows mem down to 700 or so
[10:36 AM] skippysk8s: anyhow, it might help our smaller computer owners if the ligand shows everything, but only "counts" the cells near the binding area
[10:36 AM] beta_helix: Yes, that is a good point.
[10:37 AM] RockOn: CPU still bouncing around from 29% to 36%
[10:37 AM] Susume2: I keep undo graph at 85 and undo mem 75%, and 800MB is a common RAM footprint for me
[10:37 AM] beta_helix: I've often wanted Foldit to only visually show the very far off frozen sections of spike (for example) and have Rosetta just ignore those atoms entirely.
[10:38 AM] RockOn: I'm still getting No Response from time to time
[10:38 AM] skippysk8s: it does help to try and fit the key into the lock. For example, JoannaH found a great 3 helix log with a spike that got an extra hook. it was pretty cool
[10:38 AM] beta_helix: It turns out that this is non-trivial to do.
[10:39 AM] beta_helix: Indeed, Skippysk8, I just meant the regions that are so far away they would have no interaction at all.
[10:39 AM] skippysk8s: we appreciate that...
[10:39 AM] skippysk8s: what can we do better?
[10:40 AM] skippysk8s: I'd be fine if one of my bad folds was presented as "what not to do"
[10:40 AM] beta_helix: That is a tough question, because you are all doing great! Any deficiencies are on Rosetta and our end!
[10:41 AM] beta_helix: Skippysk8, I think bkoep does that very well in his Lab Reports: showing what works and what doesn't.
[10:41 AM] Susume2: I loved the TIM barrel challenge - if you guys ever see a cool player fold and want us to try more of that shape, you could play it that way - a suggested but completely optional shape
[10:41 AM] skippysk8s: I know you are all working flat out, but feedback on the good and bad is highly appreciated. Lexie was great -- maybe she has some things she'd like us to try as a challenge
[10:41 AM] beta_helix: It really is a question of us finding the balance between filters that are scientifically accurate... but don't kill your game. (h memory/speed/fun-wise)
[10:42 AM] beta_helix: Those are h great ideas! I'm adding them to the novel of excellent suggestions today
[10:42 AM] RockOn: I'm doing a reboot to see if things change...will report in a few mins.
[10:43 AM] beta_helix: Thanks RockOn!
[10:45 AM] Susume2: in fact a slightly perturbed foldit player design could be an alternative to revisits for beginner-friendly puzzles - I know you need some ongoing data from revisits, but maybe alternate with player designs - pull them apart a little like you do the revisits
[10:47 AM] RockOn: I tried Susume2's idea track change and CPU went down and Ram use down 50%
[10:47 AM] Susume2: it would let us all play hands on with some designs from other people/teams, but in a category where you're not super hungry for diversity
[10:47 AM] skippysk8s: beta-helix do thank the team for getting a beginner puzzle up on covid... maybe we can give them a few things to dock and perhaps one to try and work on shape conformance.... It is good to have the change to expand our folding community
[10:47 AM] Susume2: great!
[10:48 AM] beta_helix: Good call, Susume. We'd just have to mess them up enough so that they wouldn't just go back down the their global mins
[10:48 AM] RockOn: So no reboot right now
[10:48 AM] skippysk8s: yes -- please bring up all hands.... or at least let all hands be a round 2 if we can't share across groups. I worked a couple puzzles with players not on my team. It would be good to share
[10:48 AM] beta_helix: Will do, Skippysk8!
[10:49 AM] beta_helix: All Hands in the past didn't really work well, but that was before design. I think it would be worth just trying it as a new puzzle (rather than the All Hands mechanic we had)
[10:49 AM] alcor29: Is there anything that can be done to speed up the feedback cycle. It is frustrating to be on round 9 of the C19 not knowing what seemed to work better than others.
[10:50 AM] skippysk8s: I understand that first round in design should get as many ideas as possible.... but then working together would help
[10:50 AM] beta_helix: alcor29.. we feel you on that one! Every Foldit meeting we are begging for feedback on previous puzzles.
[10:50 AM] beta_helix: But science is slow, and covid-19 has slowed things down a lot more
[10:51 AM] beta_helix: Luckily, things seem to have finally been sorted out... so fingers crossed that we'll get results soon!
[10:52 AM] beta_helix: Skippysk8, I completely agree with you.
[10:52 AM] beta_helix: The key is to make sure that any starting puzzles aren't so trapped in their local minimum that there is no way to improve the score... that has often been the issue with starting from high-scoring structures.
[10:53 AM] skippysk8s: maybe pull it away and make us redock lol.... we are getting to be good at that
[10:53 AM] beta_helix:hahahahahhahahaa
[10:56 AM] RockOn: Sure wish it were a 2-way chat that is going on!
[10:57 AM] alcor29: Has foldit ever tried the cooperative model instead of the competitive gamesmanship model?
[10:57 AM] beta_helix: alcor29, w.r.t what works better than others... that has been one of the main elements of the Lab Reports
[10:57 AM] beta_helix: We participated in WeFold
[10:58 AM] beta_helix: We did, though, alcor29 https://fold.it/portal/node/986517
We messed up the All-Hands puzzle yet again!
[10:58 AM] beta_helix: but it did not go particularly well.
[10:59 AM] beta_helix: We have somewhat resorted to using the "Share with Scientists" feature, in order to get models that might not be the top scoring ones.
[11:00 AM] beta_helix: RockOn, do you not see my replies to you?
[11:01 AM] alcor29: There are many smart and capable people here but I've always wondered if they only concentrated of the results instead of the score and the group competition what the results would be. Not as a partial experiment but as a total citizen science project.
[11:02 AM] Dhalion: I have never share a low scoring design
[11:02 AM] skippysk8s: ah, defintely do... I forgot to max out segments about a year ago and got a beautiful pringles fold. It scored 5th in the contest
[11:03 AM] beta_helix: It's a valid concern, and a tough balance. I honestly feel that if we had started Foldit as just a Citizen Science project, where you just participate without rankings, leaderboards, etc... we would have still gotten a lot of promising results. But I think the human competitive element adds a lot to the motivation and to the results. There is a figure in our first Nature paper's Supp Section that shows this... let me try to find it
[11:04 AM] alcor29: When only a partial experiment, game players still retain their 'secrets' and certain 'questionable' behaviors. But I get you.
[11:04 AM] beta_helix: Nature 2009
[11:05 AM] beta_helix: So this ugly figure shows the lowest Rosetta energy PER TEAM over time (in days)
[11:05 AM] alcor29: Interesting.
[11:05 AM] beta_helix: You can see that many teams flattened out (hit their high score) around days 2-3
[11:05 AM] Susume2: (lower is better, right?)
[11:05 AM] beta_helix: ...except for the cyan team! (Yes, lowest energy = high Foldit score. Thanks!)
[11:06 AM] beta_helix: Once the Cyan team suddenly was at the top of the leaderboard, bam! Everyone started working overtime
[11:06 AM] beta_helix: (shown as the yellow rectangle)
[11:06 AM] alcor29: So maybe only 2-3 days should be allowed to avoid overrefining?
[11:06 AM] beta_helix: We have indeed discussed this very often...
[11:06 AM] beta_helix: but not everyone can play Foldit 24/7
[11:07 AM] eaglgenes101: At 2-3 days, I'd stop polishing existing solutions and start trying other possible avenues
[11:07 AM] eaglgenes101 Which may or may not be effective
[11:07 AM] beta_helix: The 7 day window (or longer in certain cases, like the Monkey Virus one) is to ensure that everyone has the opportunity to play at least a few days.
[11:07 AM] beta_helix: eaglgenes101, that is exactly what you want to do!
[11:07 AM] skippysk8s: actually, our team enjoys the end game...we cross from the Ural mountains through the US with an occasional Australian. So we take the last few days for fun
[11:08 AM] alcor29: Good discussion. Many thanks beta_helix.
[11:08 AM] beta_helix: That was actually the motivation for our short-lived Exploration puzzles, and the Move Limit.
[11:08 AM] alcor29: Hope you do it again sometime.
[11:08 AM] skippysk8s: thanks beta helix
[11:08 AM] beta_helix: To force you to try a completely different fold, because it's very likely that your top score is stuck in it's local minimum.
[11:08 AM] beta_helix: Me too! Thank you all!
[11:09 AM] skippysk8s: well, just leave us some play time lol
[11:09 AM] Susume2: thanks beta!
[11:10 AM] beta_helix: Thank YOU are for your great suggestions, I'll bring them to Monday's Foldit Team meeting! Take care everyone, and keep up the great folding...

agcohn821's picture
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Joined: 11/05/2019
Groups: Foldit Staff
Office Hours 5/26- led by Horowsah

[4:00 PM] horowsah: Hey all- just wanted to say that my "office hour" today is officially starting. This means that I can try to answer questions for the next hour. A couple disclaimers- I didn't put together the puzzles that are currently up so I'm not super familiar with their details, and I'm not a COVID-19 expert. My expertise is more biochemistry in general.
[4:01 PM] Formula350 Hello :)
[4:01 PM] Jeff101: hi
nspc hi !
[4:02 PM] ipatrol: awwww
[4:02 PM] Jeff101: I've got a question about b-strands. Are the ideal zigzag structures stable if there are no hydrogen bonds?
[4:02 PM] Jeff101: like what do b-strands look like before the hydrogen bonds form?
[4:03 PM] horowsah: let's see if this answers the question- b-strands are the most extended form possible of a chain of residues
[4:03 PM] horowsah: so when it forms h-bonds to form a sheet, it's basically the same shape for each strand before and after
[4:03 PM] horowsah: just now with h-bonding
[4:04 PM] horowsah: in real life, that can happen, but it will be very dynamic and moveable
[4:04 PM] horowsah: there's a class of proteins called Intrinsically Disordered Proteins that are kind of like that
[4:04 PM] horowsah: is that answering the question?
[4:05 PM] Jeff101: when the b-strands form h-bonds, do they start near the b-hairpin bends or farther from the bends?
[4:05 PM] ipatrol: Is there any way to ensure that puzzle solutions will be specific to the target and not just bind to other common protein motifs?
[4:06 PM] horowsah: @Jeff101 hmm- that's a question that I don't know a firm answer to, but I'm guessing it's not known for most proteins. But my thought would be that it would in most cases likely start from the loop and move outward
[4:08 PM] Jeff101: I've read some about denaturation studies. Seems there are many different ways to denature sheets (chemicals, temperature, pulling on the ends).
[4:09 PM] horowsah: @ipatrol: this is the big challenge of foldit in general. To have lots of different puzzles with different facets, it becomes hard to make it as specific for each case as we want. This is definitely an active area of development for the types of COVID puzzles we've been running. My thought is that the work Foldit players are putting in is great, but that there's definitely room for improvement to make this aspect work better from the game side.
[4:09 PM] ipatrol: A strong oxidizer will denature darn near anything
[4:09 PM] horowsah: Yeah, denaturation is a big deal in protein folding studies
[4:09 PM] horowsah: I've used at least four methods of doing it in my lab work, and there's tons more
[4:10 PM] Jeff101: do they all show the same intermediates?
[4:10 PM] ipatrol: I think urea or a gunaidinium salt is usually the least destructive way of denatuging proteins at room temperature
[4:10 PM] ipatrol: *denaturing
[4:11 PM] wboler: Would it be too difficult to add filters for protein motifs we know won't work out?
[4:11 PM] horowsah:that's a good question- in general, this is a point of discussion as to whether all forms of denaturation are created equal, or even physiologically relevant
[4:11 PM] Jeff101: which way agrees best with molecular dynamics calculations?
[4:11 PM] ipatrol: Well I mean, if it'll kill you, it's probably not very physiologically relevant :-P
[4:12 PM] horowsah: that depends who you ask For example, oxidation is a common protein unfolder in cells. So that one's important. Does it show the same intermediates as temperature denaturation? Probably yes in a lot of cases, but not all.
[4:13 PM] horowsah: @wboler: i know there's been a bit of discussion on that idea, but it's practically really difficult because there's so many different ways to do something that isn't great
[4:14 PM] ipatrol: Hmm, I wonder, would it be possible to modify the game to allow us to play with some non-standard amino acid as sidechains?
[4:15 PM] Jeff101: like phosphorylated ones
[4:15 PM] horowsah: to the urea or guanadinium question, these are the most common ways to denature proteins in a lab environment without changing temp. The reason is because it's the easiest to reverse and it usually won't chemically modify the protein outside of unfolding it (and maybe causing it to aggregate)
[4:15 PM] Formula350 --- Poster child for "How to Do Stuff in a Not Great Way" :P
[4:15 PM] wboler: Would it be possible to train a neural network somehow for things that don't work? My guess is one of the limitations would be available data. Maybe some other AI mechanism.
[4:16 PM] ipatrol I'm afraid to ask, Formula350
[4:16 PM] Jeff101: what experimental technique is best for monitoring hydrogen-bonding between b-strands?
[4:17 PM] horowsah: non-canonical amino acids! In theory, they do work in Foldit, but we don't give puzzles on them hardly ever. I'm not sure if there's a specific reason why, just the science hasn't trended that way yet. The one thing is that if we're trying to design something, it's harder to put non-standard amino acids in proteins than the regular ones in the lab, so it usually leads to things that will be harder to implement outside a computer
[4:17 PM] nspc this is high level questions yes oO
[4:18 PM] Formula350 I don't follow what's going on either, don't worry :P
[4:18 PM] horowsah: @wboler on the AI- there have been a few attempts at similar things, but they've not gotten too far. It seems to me like the way Foldit players do things is especially hard for a computer to learn
[4:19 PM] jmbrownlee333 If I could ask a completely unrelated question, are there plans for small molecule design and coronavirus? I am thinking about a viral protease target, most specifically.
[4:19 PM] horowsah: @Jeff101: best technique for monitoring h-bonds: if you want a static picture of it folded, then usually crystallography, but NMR and cryo-EM do a good job. If you want to see it wiggle and jiggle in solution, then NMR is usually the way to go.
[4:20 PM] horowsah: small molecules! I'm sure that's on the minds of the people working on that aspect of Foldit long-term (because it's on everyone's minds right now), but I really don't know if it's something on the horizon there or not.
[4:20 PM] jmbrownlee333 it has been ages since we had a small molecule puzzle.
[4:20 PM] serca How do I find a protein with unknown tertiary structure (not listed in pdb) that has known environment (so I wouldn't try to fold a transmembrane protein with Foldit)? Is it really hard to find one?
[4:21 PM] horowsah: @Serca: maybe uniprot.org?
[4:22 PM] Jeff101: @horowsah what projects do you work on? that might help us ask better questions
[4:22 PM] horowsah: @jmbrownlee333: small molecules present a whole different scientific set of problems than regular foldit puzzles, so it's hard to get it just right h from a scientific game development side, and from the perspective of letting players know what is the best way to tackle those problems
[4:23 PM] horowsah: so it's something that is still under heavy development
[4:23 PM] serca never heard about that site, thank you
[4:24 PM] horowsah: what projects do i work on? Lots of things...
[4:24 PM] horowsah: within foldit, i tend to work mostly on educational tools and integrating crystallography and cryo-EM tools
[4:24 PM] horowsah: but I have a wet lab that studies how nucleic acids impact protein folding and aggregation, which I'd love to do in Foldit someday
[4:26 PM] horowsah: @sarca: uniprot is my go-to whenever i hear about a protein that i need to learn more about and know nothing about it
[4:26 PM] Formula350: How well do 310 (3-10?) Helices fold in the lab (say, compared to the traditional alpha helix we use in the game), and does the Alpha Helix do the best or is there another helix type that does similarly well?
[4:27 PM] serca: Do you know how the Foldit Remix database is generated? When I try Remix tool I often get glycine and proline forming a shape that is detected as helix by Foldit autostructures. I read in a paper that glycines and prolines are pretty common in transmembrane helices because the environment is not that agressive to break the secondary structure. Is that the reason why Remix tool tends to make helices from h these AAs?
[4:27 PM] ipatrol So yeah, I understand the difficulty with synthesizing some non-canonical AAs. I think it's pretty easy to pin arbitrary AAs to the end of an existing protein though, so maybe they can be allowed for just the ends?
[4:28 PM] horowsah: @Sarca: sorry, I don't know much about the details behind remix. I can't be too much help on that one
[4:28 PM] Josh: Dang y'all ask a LOT of good questions! For the record, this all goes over my head too =P
[4:29 PM] horowsah: @Formula350: I don't know specifically how well 310 helices do in designed proteins, but they're pretty rare in natural proteins, presumably for good reason. One thing to know is that Rosetta (which is the scientific engine Foldit is built upon) tends to have a love of alpha helices beyond what nature does. They are the most stable regular secondary structure, but it's not always the best for every scenario
[4:30 PM] horowsah: @ipatrol: yeah, ends of proteins are easier to modify than in the middle, but that really restricts what you can do with them. It's way more fun to put them all over the protein, just harder. Still, that does sound like a fun idea to explore in future puzzles.
[4:31 PM] Formula350 I accidentally made one a couple weeks back, which piqued my interest. Then my fold on NSP6 Prediction we're working on ended up creating a 310 on its own, which certainly gave me pause. Thanks :)
[4:33 PM] Jeff101: when you get a raw set of cryo-EM data for a multi-protein complex, how do you pick out which proteins go where?
[4:33 PM] Jeff101: how do you decide what to trim from the EM cloud?
[4:33 PM] horowsah: So there are tools that are used called segmentation tools, and they're job is to help you find gaps in the density where it looks like two proteins come together
[4:34 PM] horowsah: That's typically the first thing one does with a cryo-em map
[4:34 PM] Jeff101: are you working on any tools to help us solve ED/EM puzzles in Foldit?
[4:34 PM] horowsah: Then once it's been split up, it becomes a rather tough problem of figuring out which protein could even go where
[4:35 PM] serca And returning to the jeff's question about beta-sheets. Is that correct that even without H-bonds formed, beta-sheets tend to form extended straight lines? How likely loop-biased AAs tend to form that kind of straight lines?
[4:35 PM] horowsah: to my understanding, this is mostly trial and error for most people. Start building something and then figure out which amino acids it is later. it used to be that the maps weren't high enough res to do that, but now it's possible. Before, you'd have to do things like attach antibodies to different parts of your structure to see what went where.
[4:36 PM] ZombieRaccoon: Is there any possibility of being able to color the cloud with a paint program or something ? I think it would be very helpful to deal with it in small chunks and try to note areas by coloring bits of the cloud
[4:36 PM] Jeff101: we had a puzzle #1667 with too much density. I think its ED cloud was for perhaps 10 proteins, and we were supposed to find where a single protein fit into it. We didn't know the sequence for the 9 other proteins there.
[4:36 PM] Jeff101: https://fold.it/portal/node/2007726
[4:36 PM] horowsah: @Jeff101: have you guys gotten a puzzle with the new radius tool for ED/EM yet? I actually can't remember.
[4:37 PM] Formula350: I loaded a Beginner ED puzzle a week or two ago and there was a Radius slider as I recall. Not sure if that's been there or brand new, though.
[4:37 PM] horowsah: @Serca: so prolines for example tend to not be in beta sheets because they will cause a kink. Glycines are also usually too flexible. The other amino acids that don't show up in sheets often actually have more to do with the side chains and how they fit, usually.
[4:38 PM] serca: Formula350 i guess you got 3-10 on nsp6 because hydrophobis deformed the helix pretty much, trying to get buried
[4:38 PM] horowsah: Ah yes, 1667. We really weren't sure what was going to happen with that puzzle, but we thought players might like a taste of what the whole problem was like before it gets broken up.
[4:38 PM] Jeff101: I think 1797 was the last ED puzzle we got. It was in February.
[4:39 PM] horowsah: So the radius tool is one to definitely use if you haven't before in ED puzzles. We have some more tools for ED we're starting on, but there's no real timetable for them yet.
[4:39 PM] ZombieRaccoon: I like the ED puzzles, just have a hard time keeping track of area
[4:39 PM] horowsah: On ED puzzles, I tend to use Q a lot
[4:40 PM] horowsah: That's the easiest way for me to keep things in the right parts of my screen with the density
[4:41 PM] Formula350 Might be, Serca, but there's not a whole lot of them on the one that turned 310 lol (mind you, it's less 310 looking currently, than it had been 2 days ago)
[4:41 PM] Formula350 IMAGE: http://fold.it/portal/files/chatimg/irc_817348_1590532907.png
[4:42 PM] Jeff101: below is a feedback I wrote after puzzle 1667 with ideas for ED Puzzles.
[4:42 PM] Jeff101: https://fold.it/portal/node/2007742
[4:44 PM] serca: Formula350 i got some 3-10 like helix too near the phenylalanine parts of the helix
[4:44 PM] horowsah: I remember that feedback. it's interesting, the way foldit has in the past done ED puzzles is really different from how crystallographers/em people do it. For example, I never use labels, but that's because I always thread the backbone first, and figure out sidechains later. However, in ED puzzles so far, we don't let players do that
[4:44 PM] horowsah: If you're curious as to the reason, it's hard to enforce the "right" sequence if we give you a design puzzle
[4:45 PM] Formula350: That one in the screenshot is #49 (I deviated after running ""FormPRED"" on it lol)
[4:47 PM] ZombieRaccoon: Have you considered using a generic em cloud for design puzzles to define where the designed protein should be, and penalize parts outside the cloud
[4:48 PM] ipatrol: Isn't that already a puzzle type?
[4:48 PM] horowsah: I've actually done that with classes before. I've gotten good feedback and the fun level, but it tends not to produce the best science.
[4:49 PM] ZombieRaccoon: Bummer
[4:49 PM] horowsah: I'm still working on a way to make it better, though!
[4:50 PM] Jeff101: why doesn't Foldit let players thread the backbone in ED puzzles?
[4:51 PM] horowsah: So threading the backbone would be like having a design ED puzzle in which you first thread it, then change the amino acids. In theory, this should work, but it requires a ton of detailed mutation work after the fact not to what would be most stable, but whatever the protein has originally. That means things like auto-mutate don't work right, and the score function will penalize you for getting the correct sequence.
[4:52 PM] horowsah: So we'd have to put in a sequence filter on top of it, but not that would outweigh the other important things in an ED puzzle... not easy
[4:52 PM] serca: horowsah is there any characteristic of the helices/sheets like having different degrees of freedom comparing to the loops? I am trying to make the SS prediction in Foldit with getting some statistics about how they Remix in Foldit. I've noticed that the are some AAs sequences that have much more solutions from Remix database than others. That is correct for helix-propensity AAs, so I wonder if that is correct for sheets. What do you think about ponte
[4:53 PM] horowsah: When you say different degrees of freedom, could you expand on that?
[4:54 PM] ipatrol I would guess he means in parameter space terms
[4:55 PM] Jeff101: maybe remix gives more possible solutions for loops than for sheets than for helices
[4:55 PM] horowsah: so i think it was designed to give more for loops
[4:56 PM] horowsah: as to sheets vs helices, i'm not sure. Building good loops is notoriously tough.
[4:56 PM] Formula350 (Serca, for the record, your message cut off at "What do you think about ponte...")
[4:57 PM] Jeff101: for threading ED, could we start with a poly-alanine protein, fit its backbone in, and then mutate to match the desired sequence?
[4:57 PM] Jeff101: or poly-gly?
[4:57 PM] horowsah: yep, that's the way it would work
[4:57 PM] horowsah: i'll work on seeing if we can give that a try
[4:58 PM] Jeff101: the mutation wouldn't be that much computation, because the AA's would always follow a certain sequence
[4:58 PM] Jeff101: if one sequence doesn't match, just shift it along the polypeptide until it matches
[4:59 PM] horowsah: I have to head out in a minute y'all, so maybe just one more question if anyone has one?
[4:59 PM] Formula350 Sorta followup to "good loops are notoriously tough" (partial ramble here, I apologize) If ideal loops play an important role in our proteins folding in a lab, would it perhaps work better if we could instead work on an "Asymm Trimer"? Being able to make three individual helices that all want to strongly bond together, and effectively work as a Monomer, but being Asymm would then still let us determine one side as the docking side for the target (same as how we design what we do already). Or would this be too easy get destabilized and fall apart?
[4:59 PM] Jeff101: phosphates on sidechains
[4:59 PM] :mib_hgy8xr: @Jeff101- there was a puzzle like that 5 years ago: https://fold.it/portal/node/2000180
[5:00 PM] Jeff101: (thanks mib)
[5:00 PM] horowsah: Asymm trimer, like as three separate polypeptide chains?
[5:01 PM] Formula350 Yea, basically. Not connected by anything in the puzzle since they would be effectively individuals, and created individually, but later introduced next to each other to bond.
[5:01 PM] Marsfan--Formula350 I just had a crash trying to run all filters on 1840. What files do I need to send and how should I send them?
[5:02 PM] Formula350 Mars: Did you copy out the log.txt and/or debug.txt before starting Foldit up again?
[5:02 PM] horowsah: Practically, that would be pretty hard, simply because you'd have to co-express h proteins simultaneously in E. coli to make them, which increases the number of things that can go wrong by some large number. But there are applications for things like this out there. Is it easier than finding a good loop? I'd say probably not in most cases.
[5:02 PM] marsfan: Copied it out
[5:02 PM] horowsah: Ok, I have to head out- thanks all!

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hours on 6/11/20 led by Bkoep

5:02 PM] bkoep:: Hi everyone! I'm looking for office hours.
[5:02 PM] serca: i typed "11pm friday pst zimbabwe" according to formula350 message about friday and got no right time except google links to converters
[5:02 PM] bkoep:: I'm late and I can't find the office
[5:02 PM] formula350: For example, when I'm at the cabin (in Alaska) on my hotspot, sometimes I'm located in Seattle.
[5:02 PM] wboler: I'm guessing you forgot to bring donuts as well?
[5:02 PM] bkoep:: Is #veteran right? Can we set up an office here?
[5:02 PM] susume:: this sounds like 90% of my bad dreams
[5:02 PM] formula350: Yep the office is here.
[5:03 PM] formula350: You can't see us becauase we're all in our cubicles.
[5:04 PM] bkoep:: Okay, great!
[5:04 PM] bkoep: I'm bkoep:
[5:04 PM] bkoep: I'm a scientist on the Foldit team
[5:04 PM] serca: typed in google: "2:00pm GMT here" with no proxy and got 17 hours mistake. pretty sure my timezone in windows is +-1 hour from my ip timezone
[5:04 PM] bkoep: I'm here to answer questions and chat about proteins
[5:04 PM] serca: hey bkoep
[5:05 PM] serca: bkoep- why do we have so few prediction puzzles of the proteins with unknown and unpublished structures? can we have more of them? prediction is very interesting, what is the problem with getting that kind of puzzles?
[5:05 PM] wboler: Do you have any plans on making a "continuous" version of the BUNS filter? The discrete stops seems to be overly harsh.
[5:06 PM] wboler: steps* even
[5:06 PM] bkoep: Good question @serca
[5:07 PM] bkoep: The short answer is, we think Foldit is most useful for protein design problems
[5:07 PM] alcor:29 Does Buns count buns in the core also, not just the interface?
[5:07 PM] serca: bkoep: so, de-novo only? no hope for the real prediction?
[5:07 PM] formula350: It counts them wherever they are, alcor:
[5:08 PM] alcor:29 Tx bkoep:
[5:08 PM] bkoep: @serca: how do you mean de novo vs. real prediction?
[5:08 PM] bkoep: @wboler: that's an interesting question about "continuous BUNS"
[5:09 PM] wboler: My line of thinking is attributing some sort of "distance" function to how close we are becoming to creating a BUN.
[5:09 PM] nspc: IMAGE: http://fold.it/portal/files/chatimg/irc_959223_1591830575.png
[5:09 PM] bkoep: I see
[5:10 PM] formula350: lol alcor. I know but... here's an example (to the right of my Pin)
[5:10 PM] formula350: IMAGE: http://fold.it/portal/files/chatimg/irc_817348_1591830613.png

[5:10 PM] bkoep: Well, what it really comes down to, with BUNS, is whether or not the polar atom can make a hydrogen bond
[5:10 PM] serca: prediction puzzles is something with no pdb records. de-novo proteins is something very different that has no direct connection/links to its structure
[5:11 PM] bkoep: And it's true that H-bonds come in all different strengths and energies
[5:11 PM] bkoep: But the gradient between "can make an H-bond" and "cannot make an H-bond" is pretty steep
[5:12 PM] serca: my pc is not that good to new proteins design and i like to make something like prediction job on the puzzles with inlown secondary tertiary structure
[5:14 PM] bkoep: What I mean is, very small changes in atom position can yield a huge difference in H-bond energy
[5:14 PM] serca: *with unknown secondary/tertiary strcuture
[5:14 PM] wboler: True, I just wasn't sure if there was a better way. I did something similar for my master's thesis.
[5:14 PM] spvincent: IMAGE: http://fold.it/portal/files/chatimg/irc_3010_1591830885.png
[5:14 PM] wboler: (Not related to protein folding)
[5:15 PM] bkoep: @wboler, well now I'm curious! Can you say more?
[5:16 PM] wboler: I did work on optimizing the best placement of radio antenna with respect to "zones". If we gave the algorithm discrete zones, it would constantly get stuck in local optima. To guide it, I created a mix between continuous and discrete: small "energy" that grew the closer a zone edge was reached, until constant fitness for reaching within the zone.
[5:17 PM] wboler: It made me wonder if something similar could be done for BUNS, but I wasn't sure how hard that would be.
[5:18 PM] bkoep:: @serca: I see. Unfortunately, I think the prediction puzzles are just not as fruitful, scientifically (compared to design puzzles).
[5:19 PM] bkoep: So if we have to focus our efforts, we'd like to focus it where we can make the greatest contributions.
[5:20 PM] formula350: If BUNS aren't specifically your area, that's ok, but my own BUNS related question is: Would it be possible to pre-process the target by loading the ENTIRE protein with the BUNS filter, then remove them from the target in our puzzle? That way, the ones that show up by default (ie the 15 on 1846) would be factored out, thereby eliminating a bunch of visual clutter.
[5:22 PM] susume: some of those are reachable by the foldit design tho, would not want them factored out
[5:23 PM] jmbrownlee333: I am hearing that you no longer think that crowd sourcing is a way to solve the "protein folding problem". Is that true?
[5:23 PM] formula350: Granted, but if they aren't BUNS when the entire target protein is present, then they shouldn't technically be anything WE have to worry about.
[5:23 PM] bkoep: @wboler: cool! In that sense, I guess a continuous BUNS score would be really helpful for gradient descent (wiggle)
[5:23 PM] bkoep: The problem there is that BUNS calculations are really slow
[5:24 PM] alcor: 29: I had asked because I thought the interface buns interfere with docking. The others might prevent proper folding but some of the others on the perimeter might bond with water.
[5:24 PM] wboler: That's what I gathered
[5:25 PM] formula350: Yea, my question was quite directly related to what you had asked alcor :) I know that the Target's default BUNS cause a lot of confusion for players. So I figured if some of them didn't technically exist in the entire Target Protein, then having them omitted would help us understand.
[5:25 PM] bkoep: @formula350: Yes, that's a feature we'd like to add to the BUNS objective. It did not make it into the 1st generation BUNS prototype.
[5:26 PM] formula350: Ah that's great news! Thank you :)
[5:26 PM] serca: @serca: I see. Unfortunately, I think the prediction puzzles are just not as fruitful, scientifically (compared to design puzzles).
[5:26 PM] serca: Not that fruitfull to what? We now have 2 de novo puzzles and 1 revisting puzzle. Is predicting a protein with unknown scructure is worse than all that three puzzles? So predicting puzzle is even worse than pretty senseless work on a puzzle with known structure?
[5:27 PM] bkoep: Like @susume: says, we'd want to be careful about BUNS that can be addressed in the target, so we wouldn't get too fancy—just a setting to let us exclude specific residues from the BUNS calculation
[5:27 PM] susume: is the coordinate system for the BUNS voxels anchored on the locked protein? or can it move when our protein moves? some players observe BUNS changes far from where they just made a minor change, I wondered if it is due to the voxels moving
[5:28 PM] serca: i am ok with the de-novo puzzles, just cannot undeerstand how revisting puzzles are better than precition ones
[5:29 PM] wboler: Oh yeah, can we have an API to count bonds and buns programmatically in recipes?
[5:29 PM] serca: is that really the problem to find protein with the unkown structure? what is t you algorithm to find one?
[5:29 PM] wboler: (Unless something like that already exists and I'm missing out)
[5:29 PM] formula350: That may be a Josh and Neil question, I'm not sure.
[5:30 PM] jmbrownlee333: Here is a question from a player who can’t be here just now. Skippysk8 wants to know how to think about shape complementarity, vs overall square angstroms of the interface, vis specific electrostatic interactions at the interface.What’s more important to the design.? How close to atoms need to be at the molecules interface?
[5:31 PM] bkoep:: @jmbrownleee333, I'm not saying that crowd-sourcing is useless for protein structure prediction. But I'm convinced that Foldit players can make a greater impact with protein design.
[5:32 PM] jeff101: how do you plan to use our results from puzzle 1847? it seems like you already know what the structure should be.
[5:32 PM] jeff101: 1847 is the ED puzzle for the player-designed protein
[5:33 PM] serca: bkoep: that sound like that you won't have any prediction puzzles here anymore.
[5:34 PM] susume:: I had asked bkoep for 1847 just for fun, since it's a foldit player design we haven't played before
[5:34 PM] serca: does it mean there is no need in any predictionion puzzle solution?
[5:35 PM] formula350: Maybe it may be relevant and clear up some of serca:'s confusion (which also touches on your answer to JMB): On the submitted predictions on say ORF8/6/3, what percentage of our results have proven useful?
[5:35 PM] formula350: (as I think what we may need to hear is: we basically suck at prediction and our results show it, which is why we don't get many prediction puzzles)
[5:36 PM] bkoep: @serca I see your point. A big issue with the blind prediction puzzles is that we don't have a good way to evaluate the accuracy of Foldit predictions.
[5:36 PM] serca: susume 1847 looks like a solution for you question in the last office hour about trying to use some unknown puzzles vs revisted ones
[5:36 PM] susume: serca there are many unsolved proteins, but only a few that a researcher is about to solve, or has solved and not published - if we worked on predicting the ones no researcher is working on, we will never know how well we did
[5:37 PM] Migi-irc: well formula350 my suspicion is that AlphaFold is just better than the Foldit community at prediction puzzles
[5:37 PM] susume: the coronavirus ones are good because people are working to solve them right now, we might get results soon
[5:37 PM] bkoep: In rare cases (like the MPMV protease from 2011), we have experimental data that we can use to confirm predictions.
[5:37 PM] jeff101: why not have a puzzle like 1847 before the Foldit Team solved the structure? Why not let us help you?
[5:37 PM] serca: the only question i don't understand why do we have no new puzzles with unknown sturcture, and have so much revisiting puzzles, that just seem to be scientificaly senseless
[5:38 PM] jmbrownlee333: To follow on Jeff's question.do you plan to look at the player models in terms of R and/or Free? Do player structures tend to move either of these more or less.
[5:38 PM] jmbrownlee333 ignore my question, if too wonky.
[5:39 PM] serca: susume that sounds frnakly enough. that is why i am intersting why don't we have some puzzles that scientists are really working on
[5:39 PM] susume: I think it is hard to get non-foldit scientists to share their data
[5:40 PM] wboler: My guess is the revisits have to do more with validating changes made to the program, which are useful.
[5:41 PM] formula350: I can appreciate serca:'s viewpoint. Assuming that there's no limitation on the server-end for having more than 3 puzzles running (as I know there are periodic automated submissions), it might be nice to exclude the Revisits as one of the "3", and include a Prediction puzzle, regardless.
[5:41 PM] serca: susume i even tried to find a puzzle with the known environment an unknown 3d structure and length less than 200 to work on understood that it is not hat easy to find one
[5:42 PM] serca: that is the reason of my question and that is wju i try to clear that in me next questions: i get no the clear answer from bkoep: (sorry dude, take my respect)
[5:43 PM] bkoep: @serca: It's true the scientific value of the revisited puzzles is thin. They are definitely useful for long-term, continuous benchmarking (i.e. is Foldit performance consistent over time as the software and community evolves).
[5:44 PM] bkoep:We also like the Revisited puzzles as a gateway for novice players, but that doesn't really have anything to do with scientific results
[5:46 PM] serca: and i also like the puzzles with unkown structure vs revisting ones to work as the only reason th present myself in foldit.
[5:46 PM] alcor:29 Any progress in the labs this week on Covid puzzles?
[5:47 PM] serca: but i am ok if you discriminate my 10y.o. cpu tand my hand folding skills to run just revisitng puizzles
[5:47 PM] serca: *tand=and
[5:47 PM] pc: I like design puzzles
[5:49 PM] serca: guess i like them too if my cpu is ok with all the filters
[5:49 PM] jmbrownlee333: can I re-ask skippysk8's question. Skippysk8 wants to know how to think about shape complementarity, vs overall square angstroms of the interface, vs. specific electrostatic interactions at the interface.What’s more important to the design.? How close to atoms need to be at the molecules interface?
[5:50 PM] jmbrownlee333: to=do
[5:50 PM] bkoep:: @jmbrownlee333 @jeff101 Those are good questions about the ED puzzle! When x-ray diffraction is this good, it is less work to solve the structure automatically than to set up the Foldit puzzle.
[5:50 PM] serca: or they just switch their filters to gpu, to unload my cpu
[5:51 PM] susume: (thx jmb, you understood skippy's question better than I did)
[5:51 PM] bkoep: The more interesting challenge comes from poorer quality or lower resolution data, where the automated methods fail. We hope to bring more of those puzzles to Foldit.
[5:53 PM] jeff101: if you took our 1847 solutions and removed the ED part of the scores, would the results be useful for understanding the energy landscape of the designed protein?
[5:54 PM] bkoep:: @alcor 9 Yes, the lab experiments are progressing for h the CoV spike and IL-6R binders, but I still can't give a time estimate on when we'll have data
[5:54 PM] :alcor: 29 Tx
[5:54 PM] bkoep: Frankly, I probably can't offer a time estimate until we actually have the data
[5:54 PM] alcor:29 k
[5:55 PM] jeff101 if you think of answers to some of our questions later, please make a blog post about them
[5:55 PM] serca: bkoep can you please advice any algorithm to find a puzzle with the unknown structure?
[5:55 PM] serca: I want to have some fun on the sandbox puzzle with that.
[5:56 PM] bkoep: @jmbrownlee333 @Skippysk8s That's a great question about which binder metrics to focus on.
[5:56 PM] bkoep: We don't really know
[5:56 PM] bkoep: We will try to set their relative weights to something reasonable
[5:57 PM] bkoep: But the fact is that shape complementarity, and SASA, and BUNS, and DDG, and electrostatics all show some correlation with binding success rates
[5:58 PM] jeff101 there was another binding design project about a year ago ... non-COVID ... what is the status of that project?
[5:58 PM] bkoep: For some of these, we have some target thresholds where maybe the correlation drops off
[5:59 PM] bkoep: But I'm pretty hopeful that Foldit players can optimize all of them
[6:01 PM] bkoep: The traditional way we design binders is pretty inefficient: we spend a bunch a computational time generating 1M designs without optimizing these objectives, and then we check which of those 1M designs meet the objectives and throw out the 99% that don't.
[6:02 PM] serca: @bkoep so, no algorithm to find a puzzle with the unknown structure and known environment? no answer looks like a positive answer for that. thank you.
[6:02 PM] formula350: Do you guys/gals in the lab ever look at our designs and try to "Evo" the best candidates yourselves, or do you typically just feed them to an algorithm?
[6:02 PM] bkoep: It seems like Foldit players might be able to consciously tailor designs meet all of these criteria, instead of blindly shooting birdshot at a tiny target
[6:03 PM] bkoep: @serca Sorry, I'm not sure what you mean about "known environment"?
[6:03 PM] jeff101: cytosol vs membrane?
[6:04 PM] jmbrownlee333: or excreted.
[6:04 PM] jeff101: favoring disulfides or not?
[6:05 PM] serca: i am just talking about any structure that is not listed in the pdb is interesting. just toooooooo tired of the revisiting puzzles. but "known environment" means just hydrophobcity score.
[6:05 PM] serca: anyway i guess most of us will be happy with just any random AAs that are not listed in the pdb
[6:08 PM] serca: but the best AA sequences are made by nature. that is the reason of the feeling to talk with god while folding them.
[6:08 PM] bkoep: Oh I see. There are lots of protein sequences out there without structures. Like, the NCBI BLAST database of non-redundant protein sequences.
[6:09 PM] bkoep: And people are discovering tons of new ORFs now from shotgun sequencing experiments
[6:10 PM] bkoep: Basically, take a bucket of seawater and sequence all of the DNA in it)
[6:11 PM] serca: so what stops you do add that to our puzzles and have us to fold something really known then?
[6:11 PM] susume:: Serca you could find an unsolved sequence from ncbi and challenge players to solve it in sandbox, we won't know if anyone is right but we could compare results
[6:11 PM] bkoep: @jeff101, the IL-7R binder experiments got held up by the COVID-19 shutdown, but I think we may have some of that data soon
[6:12 PM] serca: *really unkown then
[6:13 PM] jmbrownlee333 On 1847, s there any area where the x-ray structure varied from the design more? Were loops or sheets or helices farther off from the design model?
[6:13 PM] formula350: Wonder if you can make a "Contest" using the Sandbox puzzle as a base.
[6:13 PM] serca: susume i don't like your solutions, sorry, but what is your the algorithm to find the AA sequence with unknown structure?
[6:14 PM] serca: i see foldit guys don't have any algorithm to find the AA sequence no listed in pdb and that is their problem (sorry bkoep)
[6:15 PM] bkoep: @serca You can use NCBI BLAST to check if a sequence is in the PDB
[6:15 PM] bkoep: https://blast.ncbi.nlm.nih.gov/Blast.cgi
BLAST: Basic Local Alignment Search Tool. The Basic Local Alignment Search Tool (BLAST) finds regions of local similarity between sequences. The program compares nucleotide or protein sequences to sequence databases and calculates the statistical significance of matches. BLAST can be used to infer functional and evolu...
[6:16 PM] jmbrownlee333: No like bkoep said, no way to know if you are on the right track, for who knows how long.
[6:18 PM] serca: bkoep so I want to fold a nice 150 length reisdue protein at the sandbox: what should I do to find one that is not listed in rcsb pdb?
[6:18 PM] serca: could you please tell me the buttons i have to press?
[6:18 PM] susume: Serca this is not something someone can teach you in 3 lines of chat, go read about blast and educate yourself
[6:19 PM] serca: very draft how you understand that
[6:19 PM] jmbrownlee333: @serca i have some ideas, can chat in group or offline.
[6:19 PM] jmbrownlee333: Ie PM
[6:19 PM] serca: jmb that is interesting in prespective
[6:20 PM] serca: susume: you know... i guess the reason we have no any proteins with the unknown structure is that they just don't know how to find that
[6:20 PM] bkoep: @serca I'm sorry, I cannot tell you which buttons to press. But the NCBI tools are pretty nice, I think you will find them easy to use
[6:20 PM] bkoep: Okay all, I'm sorry, I have to run

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office hours 6/26- led by beta_helix and SethCooper

Office hours 6/26- led by beta_helix: and SethCooper:

[6:00 PM] beta_helix:: Hello everyone!
[6:00 PM] donuts554: hello how are you?
[6:00 PM] SethCooper: hello!
[6:00 PM] beta_helix:: Seth Cooper and i will start off today's Office Hour
[6:00 PM] jeff101: hi
[6:00 PM] formula350: Wait it's just Beta Helix? I thought it was Gamma Helix who'd be here. :( Welp, I'm leaving then......... lol
[6:00 PM] beta_helix: Doing good, donuts554! Hi jeff101!
[6:01 PM] beta_helix: hahahhahahahhaa
[6:01 PM] donuts554: how are you seth?
[6:01 PM] formula350: :P
[6:01 PM] SethCooper: doing pretty well
[6:01 PM] formula350: First thing's first.... Chocolate or Vanilla?
[6:02 PM] formula350: And then: Who would win in a fight: Beta or Seth? :}
[6:02 PM] beta_helix: Gamma Helix would beat h of us!
[6:02 PM] SethCooper: probably a tie
[6:02 PM] formula350: Alright I've gotten all my shenanigans out of the way ;)
[6:03 PM] donuts554: Chocolate and idk
[6:03 PM] alcor29:: Question: Currently Foldit Rosetta?) does Wiggle, Wiggle sidechains, and Shake sidechains as discrete operations. Has anyone ever looked at coding that would do all three as a single fluid motion, as one might imagine happens in a real environment? Would that be desirable? If so, even doable?
[6:03 PM] formula350: Donuts we're asking THEM questions, not each other lol
[6:03 PM] donuts554: oh ok
[6:04 PM] formula350: Wiggle does "Wiggle Backbone" and "Wiggle Sidechains" at the same time. Just to point that out.
[6:04 PM] alcor29: k
[6:04 PM] beta_helix: It's all good
[6:04 PM] SethCooper: yeah, I think early on we had considered having an operation that does h shake and wiggle in one operation
[6:04 PM] beta_helix: That is a very good question, alcor29
[6:05 PM] SethCooper: but I think even at that level, it would have to alternate wiggle and then shake somehow
[6:05 PM] beta_helix: One thing that the Rosetta community noticed, and I know you have as well, is that there is often a big difference between Wiggle-Shake or Shake-Wiggle
[6:06 PM] beta_helix: That is why Blue Fuse (and Relax in Rosetta) do these alternations with different thresholds (of clash importance, for example)
[6:07 PM] beta_helix: I agree that it would be a lot more realistic to have one fluid action... like in Nature. That is what molecular dynamics simulations try to do.
[6:08 PM] alcor29: Thx.
[6:08 PM] donuts554: My Question is part of something else, but is it necessary to render aromatic compounds without the see-through holes?
[6:08 PM] donuts554: In Foldit
[6:08 PM] donuts554: I mean amino acids not compounds
[6:09 PM] beta_helix: So, here is a TRP in Foldit, right?
[6:10 PM] donuts554: Yes
[6:10 PM] donuts554: I can't see the image though
[6:10 PM] beta_helix: https://foldit.fandom.com/wiki/Amino_Acids
Foldit Wiki
Amino Acids
Amino acids (also called segments or residues in Foldit) are the building blocks of proteins. Each amino acid has a unique sidechain, except for glycine. Each protein is identified by a unique...
[6:11 PM] formula350: I looked at it, it's simply the Tryptophan as you know and love (or I guess in your case, hate lol)
[6:11 PM] beta_helix: (sorry, I'm in Discord
[6:12 PM] donuts554: ok then yes it is a TRP in FOldit
[6:12 PM] beta_helix: You can render it without the hole with the Sphere view, right?
[6:13 PM] donuts554: Yes I can
[6:13 PM] beta_helix: Are you asking if we should do the same in stick mode?
[6:13 PM] donuts554: But it its more puffy and takes more space and makes the surface covered
[6:13 PM] donuts554: Yes I am asking that
[6:14 PM] beta_helix: If you look at all these amino acids from a cartoon view, such as TRP:
[6:14 PM] beta_helix: https://en.wikipedia.org/wiki/Tryptophan
Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a non-polar aromatic amino acid. It is essential in humans, meaning the body can...
[6:14 PM] beta_helix: Then we are essentially just drawing lines for each bond... which in this case creates these 2 rings.
[6:15 PM] beta_helix: As you mentioned, if we didn't draw it that way it would make the surface covered and takes more space.
[6:15 PM] beta_helix: Our Cartoon and Cartoon Thin are designed to give you enough information about the sidechain, without so much detail that you can't see what is going on.
[6:17 PM] donuts554: Oh ok, thanks for the answer! I have another question but i'll let others ask their own
[6:17 PM] formula350: If your followup is directly related, it might be good to ask it.
[6:17 PM] donuts554: Oh ok then I'll ask it
[6:17 PM] beta_helix: There are 2 of us, so we can handle multiple questions
[6:19 PM] jeff101: one question folks were asking the other day is if Foldit accounts for pi stacking, and if so, which energy subscores reflect it best?
[6:22 PM] donuts554: I think thats kinda related to my question somewhat
[6:22 PM] beta_helix: I know Foldit does for sure... but I don't know which subscores show that.
[6:23 PM] jeff101: sorry donuts
[6:24 PM] beta_helix: I will find that out and post it in the Forum for you (unless that question was already posted somewhere)
[6:25 PM] donuts554: Its ok, I meant that I think it was related to my previous question about aromatic compounds without the holes
[6:26 PM] donuts554: The next question im going to ask is going to be a bit long because I have to describe things
[6:26 PM] formula350: We need "Arcade Mode"... With big text popups and an announcer. Displaying like: GREAT PI STACKING!! or an annoucer proclaiming "You just flipped Covid the Zinc Finger!"
[6:26 PM] beta_helix: Type away, we'll answer any other questions
[6:26 PM] beta_helix: It's funny that you mention that, formula350:, because the early versions of Foldit had that!
[6:27 PM] formula350: Donuts, just emember that Foldit can only send messages that are so-long before it gets cut off.
[6:27 PM] beta_helix: Seth, am I right in remembering that most players turned that off?
[6:27 PM] SethCooper: i think the majority of options are left on the default
[6:27 PM] beta_helix: I mean, it didn't say "Finish him!" (this Protein!)
[6:28 PM] jeff101: what things are each of you working on these days?
[6:28 PM] formula350: haha I mean, I have sounds disabled, but I wouldn't mind visual stuff, as I think it being pointed out when you create a.... "motif" (?? I guess that's what it'd be considered as), would actually be a learning experience for some of us.
[6:29 PM] beta_helix: donuts, feel free to break your posts up so they don't get cutoff!
[6:29 PM] beta_helix: Seth, you go first (your stuff is cooler ;-))
[6:29 PM] Susume: I would love it if foldit could recognize a motif - it mostly crows about smaller things like H bonds
[6:30 PM] beta_helix: ohhhhhh, so you mean USEFUL popups?
[6:31 PM] formula350: :P Yea, like Rank Up. However, adding some comedic flair would probably make it more appealing to the younger (or more childish, in my case) crowd since it'd provide some "action".
[6:32 PM] alcor29: A little Wagner leitmotif?
[6:32 PM] Susume: dystopian foldit popups
[6:32 PM] beta_helix:: @jeff101: Scott Horowitz and I just submitted an NIH grant yesterday to make Foldit Electron Density state of the art (ie incorporate the tools used in the best ED programs out there) fingers crossed it gets funded
[6:32 PM] donuts554: Is it necessary to have a new "View Protein" option with aromatic compounds without the holes, the proline without its hole, the thick helices as cylinders, the sheets without the zigzag contours --
[6:33 PM] Susume:drools for upgraded ED tools
[6:33 PM] beta_helix: Right?!?!?!
[6:33 PM] jeff101: I've asked questions like this in previous Office Hours. Not sure if I asked you guys.
[6:34 PM] jeff101: the papers I've seen don't generally show where the h-bonds go
[6:34 PM] beta_helix: I just want to say that I've been trying to get ED funding since I left Seattle in 2013... but it is hard!
[6:35 PM] jeff101: I hope you get the funding.
[6:35 PM] SethCooper: one thing we have been working on is something like the tutorials but more dynamic
[6:35 PM] beta_helix: Me too! I'm submitting another grant to the NSF next month as well. (edited)
[6:35 PM] Susume: do you feel like there is a "market" for foldit to work on ED? do scientists maybe feel like they're doing just fine without us?
[6:36 PM] spvincent Get the word Covid in the funding application somewhere and hopefully people will throw money at you.
[6:36 PM] beta_helix: @spvincent don't worry... it's in there!
[6:36 PM] SethCooper: (in this case "we" means mostly Josh)
[6:36 PM] spvincent good!
[6:37 PM] beta_helix: @Susume it's a very good question... but I honestly think that the issue has been how unorthodox Foldit is (especially when asking for grant money)
[6:37 PM] formula350: Call us a Think Tank and it might go over a bit better?
[6:38 PM] donuts554: --to eliminate all convex angles in sidechains, so a lysine pointing straightout is not a zigzag, instead its a striaght line, a valine looking like a orange triangle, and a arginine looking like a blue triangle on top of a blue pole with blue ends --
[6:38 PM] beta_helix: You can imagine that when a panel has 100 applications and only enough money to fund 10... it's not hard to believe that they will go with (what they feel is) the "safer" bet.
[6:39 PM] beta_helix:: formula350: u know, you are not far off... because a lot of grant reviewers reject the notion of "gamers"
[6:40 PM] beta_helix: I talked to a Program Manager at the NSF, and he agreed that if I only refer to Foldit players as "citizen scientists", it would be received a lot better! sigh
[6:40 PM] donuts554: --and to have any H-bonds or disulfide formed between amino acids more solid and widened so that it looks like the amino acids are actually stuck together?
[6:41 PM] beta_helix: (Anyway, I can ramble on about this for ever... so I'll stop and answer donuts)
[6:41 PM] beta_helix: @donuts disulfides are a very good example of what you are talking about
[6:41 PM] beta_helix: Because those are some very strong bonds!
[6:42 PM] beta_helix: Seth, jump in here, but I think one of the reasons we didn't go with the h-bond glue (for example) is that we do want you to try different topologies.
[6:42 PM] donuts554: Not glue
[6:42 PM] Susume: given how long some of us have been playing, we've almomst become a "curated collection" of citizen scientists (kinda like being pickled I guess)
[6:43 PM] donuts554: I mean like in this new view protein option, when you pull the two amino acids apart, the solid rod connecting the two charged atoms disappears
[6:43 PM] beta_helix: If you have a protein with a lot of molecules stuck to one another, wouldn't you be less likely to break those?
[6:43 PM] donuts554: Like a normal H-Bond would in cartoon
[6:43 PM] donuts554: No It just looks like its stuck together
[6:43 PM] beta_helix: but that rod would look like it was almost as strong as a carbon-carbon bond, right?
[6:43 PM] SethCooper: well, I think bands can be used to hold h-bonds together if wanted, if that's what you mean
[6:44 PM] donuts554: No not hold H-bonds together, I mean, the same thing as now --
[6:44 PM] donuts554: But
[6:45 PM] formula350: It's all about "spinning" it. Electrons spin, PR spin, as does Grants for funding. In reality, you're not lying by referring to us as Citizen Scientists, or Distributed Brainpower, or Community Think Tank. In the realm of science I can't ever see "Gamer" as being taken legitimately or seriously. Some of us (Susume) have literally been so inspired by Foldit, that they've shifted their life to pursue it. So I think calling Susume a "gamer" is arguably
[6:45 PM] beta_helix: @Susume I like that term... I should use it in a grant be it would go way over their heads! Uh oh... do any grant reviewers hang out in veteran?
[6:45 PM] donuts554: The solidess used to render the bonds holding the amino acids together is used for the H-bond and disulfide bonds as well
[6:45 PM] donuts554: Basically so all bonds look the same
[6:46 PM] donuts554: only with different color of course
[6:46 PM] donuts554: and so that only h-bonds and disulfide bonds can be broken
[6:46 PM] donuts554: thats what I mean
[6:46 PM] beta_helix: Donuts, why would you want them to look the same? The reason we color some orange vs blue (as you just pointed out) is to highlight their difference.
[6:47 PM] donuts554: Yes the color stays different, but the texture looks the same
[6:47 PM] SethCooper: the hbonds and disulfide bonds are rendered a bit differently though
[6:47 PM] beta_helix: The easier it is for players to differentiate between them, the easier it is to manipulate the structure, isn't it? If everything had the same texture (or say was all loop, instead of helix/sheet/loop) then it would be very hard to visualize
[6:48 PM] formula350: Donuts if you would like the Disulfide Bond 'texture', I can make one for you to use instead.
[6:48 PM] donuts554: Yes I mean without the different rendering, same rendering for all bonds, just different colors
[6:48 PM] Susume: I think donuts is saying he wants H bonds and disulfides to be drawn like covalent bonds are currently drawn, as solid cylinders - is that right?
[6:48 PM] donuts554: Like bright cyan solid bond holding as H-bond, bright yellow for disulfide
[6:48 PM] donuts554: Yes! That's what I mean formula
[6:49 PM] donuts554: They are bonds, and they should be treated fairly
[6:49 PM] donuts554: It follows the "bond" definition
[6:49 PM] beta_helix: But they are different bonds...
[6:49 PM] donuts554: It's just their strengths are different
[6:49 PM] formula350: I think you mean Susume? He wants everything to be "solid". Aromatics, Helices, etc. Not this "there's a gap, so something could arguably pass-through it"
[6:49 PM] donuts554: Like you have chemical reactions breaking bonds and making bonds, like in 1855
[6:50 PM] SethCooper: we figured they were different enough they should look different
[6:50 PM] SethCooper: plus, we are often encouraging the creation of hbonds so they are like a "goal" in the game
[6:51 PM] spvincent: Can I ask a question about filter scoring?
[6:51 PM] beta_helix: I completely agree that we are simplifying the reality of proteins... but that is done intentionally, for the exact same reason that you mentioned earlier: Sphere mode (while being more realistic) is almost impossible to fold in.
[6:51 PM] donuts554: This will make it look like there is actual chemistry, breaking and forming bonds
[6:52 PM] donuts554: Oh ok seth nvm about the bonds part
[6:52 PM] beta_helix: Take electrostatics, for example, donuts... or even water, we don't even show those at all! So this really is a cartoon version of chemistry, as opposed to making it look 100% accurate. I hope that answers your question.
[6:52 PM] beta_helix: @spvincent of course!
[6:54 PM] spvincent: I was wondering why the bonus/penalty for filters such as Buns, Core Filter, etc follows a stepwise function as opposed to being continuous. It play havoc with scripts.
[6:55 PM] spvincent: *plays
[6:55 PM] SethCooper: I'm not sure about those specifically, but some bonuses are based on discrete things in the structure
[6:55 PM] donuts554: Well the intent is not for 100% accuracy, but also for less complicated things for the eye to remember and visualize in the brain memory, and to have less rendering so that it is less laggy and therefore less crashes
[6:57 PM] spvincent: In the real world of proteins I'd expect smooth variation. A polar atom isn't either buried or unburied: it can't be that binary.
[6:57 PM] formula350: Yea, like the uh... "IE" filter. I think it's called.
[6:57 PM] formula350: Interaction Energy?
[6:58 PM] SethCooper: for example, if a bonus is based on, say, a number of bonds or a number of residues, then it's more straightforward to score based on that
[6:58 PM] SethCooper: there are some techniques use to smooth them out in some cases
[6:58 PM] beta_helix: @donuts that is a very good point that you bring up, and something that we have struggled with for a long time... especially as we try to post puzzles with bigger and bigger proteins. We actually considered going the opposite direction of your suggestion: removing most sidechain atoms, which is when we tried out Centroid Mode (I know the mention of it just made a few players sick) needless to say, it did not go well.
[6:59 PM] formula350: But I presume that it's based on actual Rosetta scoring, versus most Filters which are ad-hoc and side-calculations that would require more processing power (time) to provide "real-time" output. Is this a fair assessment, Seth?
[6:59 PM] formula350: ("that it's" referring to something like the Interaction Energy filter)
[7:00 PM] SethCooper: yeah, the filters I think can often be simplifications based on counts or thesholds
[7:00 PM] donuts554: Like the convex angles in valine and leucine are intuitvely harder to remember than as rendered as a short, filled orange triangle and a longer, filled orange triangle (cause the vertex point in that position in 3D is located in the inside of the atom according to sphere mode)
[7:01 PM] SethCooper: the early filters/bonsuses were entirely binary, as I recall
[7:01 PM] SethCooper: so adding in the steps in scoring does kind of smooth them out a bit from that
[7:02 PM] spvincent: Its quite frustrating working with proteins when you're on a boundary and e.g. the core bonus keeps flipping from 2900 to 3000
[7:02 PM] spvincent: and back again
[7:03 PM] formula350: Yea. Not having a nice Subscore to gauge what we're doing on, makes thoses, and BUNS, etc, very hard to determine whether what we're doing is "good" or "bad".
[7:03 PM] beta_helix: donuts, you might get a kick out of this (or be mortified) but some of the very early Foldit mockups didn't use actual sidechains at all... they were random shapes (or different fruit) or other cartoony representations!
[7:04 PM] jeff101: I would request the Ideal Loops Filter scores by residues in ideal loops rather than by the # of ideal loops
[7:04 PM]SethCooper: it's quite possible some that are based on thresholds could be smoothed out a bit as well
[7:05 PM] spvincent: that would be most helpful i think
[7:05 PM] formula350: A "glow" factor, or "color transition gradiant" (for BUNS/Ideal Loops, and Core Existence, respectively) would help a lot, if that's doable as well.
[7:05 PM] formula350: Acting much in the same way that the HBond line gets thinner as it grows weaker, or fatter as it gets really strong.
[7:05 PM] Susume: (just try to get funding for something that represents sidechains as bananas!)
[7:05 PM] jeff101: being able to color by specific subscores rather than the total score would be helpful
[7:06 PM] donuts554: Also, showing the glutamine, arginine, asparagine as triangles on top of poles will make it easier to recognize the pattern of the shape of the amino acids, and to make it easier for espcially even children to recognize and categorize and theorize the properties of the amino acids and compare them, intuitively.
[7:06 PM] spvincent: That reminds me: I do not like the way the Buns filter messes with the View Settings.
[7:06 PM] formula350: Yea, they're working on that VIncent :)
[7:06 PM] alcor29: Speaking of ideal loops. Is there some way of knowing whether mutating a single residue would make it ideal, instead of the sometime laborious process of trying to find a better shape?
[7:06 PM] spvincent: oh good
[7:08 PM] donuts554: (ex. Histidine would look like a blue filled pentagon on top of a blue filled triangle on top of a pole., and Asparagine and glutimine would look like blue triangles on top of poles. I think, and even I think myself too, that they make think, --
[7:08 PM] beta_helix: @donuts554 The team is working on a more specific Education version of Foldit that would be aimed more towards schoolchildren.
[7:09 PM] formula350: Trying to smash a square protein through a round target hole with their feverous mouse clicking.
[7:09 PM] beta_helix:That's what the big spiky ball is for!
[7:10 PM] formula350: Who... ME?!
[7:10 PM] formula350: IMAGE: http://fold.it/portal/files/chatimg/irc_817348_1593220214.png
[7:10 PM] beta_helix: hahahahhahahhahahaha Nice!
[7:11 PM] beta_helix: Well thank you all for stopping by Office Hours!
[7:11 PM] jeff101: will someone post a transcript on the Foldit web page?
[7:11 PM] jeff101: thanks for coming
[7:11 PM] beta_helix: We've been trying to hold them at different times, to try to spread the timezones out as much as possible.
[7:11 PM] formula350: Yes, we managed to bring donuts this time.
[7:11 PM] donuts554: "Oh! These three amino acids all have red and blue dots, and all similarly have a blue filled triangle on top of a pole! So, they may think, oh histidine is related to asparagine and glutimine, and histidine may have came from glutamine!'"
[7:12 PM] beta_helix: Yes. We are trying to post the whole transcript, rather than just a discord link. We're still working on that, so thanks for your patience!
[7:12 PM] donuts554: And they think, "So that's why Histidine and glutamine have similar properties"
[7:12 PM] donuts554: You are welcome!
[7:12 PM] beta_helix: Someone should really make an amino acid card game!
[7:13 PM] SethCooper: that sounds like a good idea!
[7:13 PM] formula350: I think Josh made an AA based Board Game (or maybe it was Proteins in general...)
[7:13 PM] beta_helix: In that case, he should make it online so we can all play together!
[7:14 PM] formula350: It's about to be released. It's on his website as Coming Soon
[7:14 PM] donuts554: I have more questions but Ill go to the next office hours
[7:14 PM] beta_helix: Sweet... can I invest in that?
[7:14 PM] beta_helix: Thanks again everyone... Thank you Seth!
[7:14 PM] formula350: @Josh @Gamma_Helix wants to invest in your new boardgame ;)
[7:15 PM] formula350: Yes, thanks Beta and Seth.
[7:15 PM] beta_helix: Thanks donuts, I look forward to them
[7:15 PM] beta_helix: Have a great weekend everyone... stay safe, and keep up the great folding!
[7:15 PM] SethCooper: yes, thank you!

agcohn821's picture
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Joined: 11/05/2019
Groups: Foldit Staff
Office hours 7/17- led by beta_helix

[2:01 PM] beta_helix: Hi everyone! Foldit Office Hours are open
[2:02 PM] beta_helix: I wanted to report back from a conference that Seth and I presented at this week (virtually, of course). It was at the biggest Bioinformatics conference, and this special session was called "Bioinformatics outside the lab: How to mobilize online citizen scientists to accelerate research" https://www.iscb.org/ismb2020-program/special-sessions#sst02
Special Sessions
ISCB - International Society for Computational Biology
[2:12 PM] lociOiling:Oiling: hi - not a very chatty crowd today
[2:13 PM] Josh: I think we forgot to advertise this, haha
[2:13 PM] beta_helix: It was posted in discord, but only once I think...
[2:13 PM] beta_helix: perhaps that's not enough.
[2:13 PM] beta_helix: It's ok, I get empty office hours when I'm on campus too!
[2:14 PM] Josh: While we have you, beta, did you get the latest newsletter? What's your scientific opinion on the top scoring results?
[2:14 PM] beta_helix: Did you trick me in here to go over your newsletter?
[2:15 PM] Josh: Nah I just want feedback on the top scores. Here are more of them:
[2:15 PM] Josh: https://foldit.fandom.com/wiki/Puzzle_1862
Foldit Wiki
Puzzle 1862
Puzzle 1862: Coronavirus Binder Design: Round 13
[2:16 PM] Josh: What feedback can you give to the players on these designs?
[2:16 PM] beta_helix: So I'm one of those "scientists" that need to move my protein around in PyMOL or Foldit...
[2:16 PM] lociOiling:Oiling not supported in png
[2:16 PM] beta_helix: It's really hard to analyze them in depth with just 2D
[2:16 PM] beta_helix: hahahahahahahhahaha
[2:17 PM] beta_helix: I'll try to get an undergrad to work on that!
[2:18 PM] beta_helix: We actually have discussed this (just before covid), where ideally we'd have a viewer on the Foldit webpage, and you could view your own models
[2:18 PM] HuubR: Was it ever considered to make a 3D viewer in Foldit (I mean, different views for left eye and right eye)
[2:18 PM] alcor29: Did anything that will affect us come out of the conference?
[2:18 PM] beta_helix: (I don't know if I'm not supposed to spill that secret, but luckily there aren't many people here today!)
[2:18 PM] lociOiling: it's been suggested, HuubR, viewers like JMol have 3D
[2:19 PM] beta_helix: @HuubR but rendering in Foldit already slows us down when it comes to large proteins
[2:20 PM] beta_helix: This would be solved if we can get Foldit VR going(edited)
[2:21 PM] HuubRWould VR reduce the workload needed for rendering?
[2:21 PM] beta_helix: @alcor29 I think it was a very interesting session, first off because it was the first time all of these games have been together in on (virtual) room... which is honestly a shame that it took 12 years!
[2:22 PM] beta_helix: @HuubR great question... I think VR would open up a bunch of new limitations, but how cool would it be to move around in Foldit with it!
[2:23 PM] beta_helix: One of the other cool things about that session is that they invited 3 speakers from the video game industry to talk about how they've incorporated citizen science games in Borderlands 3 and Eve Online.
[2:24 PM] HuubR: @pc (nspc), are you listening in?
[2:24 PM] pc: hello
[2:24 PM] beta_helix: One of the interesting points they brought up was that they've learned not to hide the science in their games.
[2:24 PM] beta_helix: Hello Hello!
[2:25 PM] HuubR: (nspc is a French game developer)
[2:25 PM] beta_helix: At first when they designed these scientific minigames (inside these massive video games) they felt they should try to mask the science as much as possible.
[2:27 PM] Susume: the same kind of nerdiness that makes gamers like to research and memorize meta and lore and character stats is the same kind of nerdiness that makes science fun and addictive
[2:27 PM] beta_helix: but they realized that was the wrong way to go about it, and players were actually interested in understanding the science behind it... that it reinforces the "WHY am I playing this?"
[2:28 PM] beta_helix: For sure, Susume! Another thing they pointed out is how many science-lovers ended up in the game industry.
[2:30 PM] pc: Yes in foldit I often ask this question to myseft (in design puzzles): "Is my protein works in real life ?"
[2:30 PM] beta_helix: C'est une question qui n'est pas facile a savoir!
[2:30 PM] pc: I know score system is not perfect
[2:31 PM] beta_helix: Opps, sorry, I had caps lock on there!
[2:31 PM] beta_helix: It's a question that isn't easy to get the answer to.
[2:31 PM] pc: And add more metrics is complex, because current metrics take lot of computation (like SASA DDG and SG)
[2:32 PM] pc: I saw lof of top score solutions that have just 3 links with target, but not realy shape complementarity
[2:32 PM] beta_helix: That is the Foldit dilemma that's we've faced from the start.
[2:32 PM] lociOiling: gotta watch caps lock on those canadian keyboards
[2:33 PM] beta_helix: We could have had a client that could easily load 1000 amino acids (like PyMOL), but you wouldn't be able to produce anything useful with it.
[2:33 PM] beta_helix: @lociOiling so true
[2:33 PM] HuubR: Now that we're talking about scoring, there's a question that has been in the back of my mind for some time
[2:33 PM] lociOiling: don't get me started on swiss
[2:34 PM] beta_helix: There is also the balance between letting you fold without filters, but then when you turn on the filter you find out all your work was useless
[2:34 PM] beta_helix: Which is worse?
[2:36 PM] beta_helix: Right now, you can think about it that we tell you this information after the fact (when we analyze your solutions). It has to be better to give you that ability... but it is still frustrating to have your hard work invalidated if you click a "check my protein-ness" button.
[2:38 PM] HuubR: I'm sure the present scoring (is it Rosetta?) is very well suited for prediction puzzles, but isn't it so that for design puyzzles, it might favor certain amino acids over others?
[2:38 PM] beta_helix: @HuubR great question
[2:39 PM] HuubR: Or certain secondary structures, for that matter?
[2:39 PM] beta_helix: It is Rosetta (there are just many different flavors of Rosetta). You can imagine that it is a lot harder to come up with an accurate score function when dealing with design.
[2:39 PM] pc: For computation we can use GPU acceleration or multithreading (but it is complex). An other idea can be : for some metrics, dont include them in ojectives but just have some recipes availables and run them to check our protein. (or a lua fonction for thoses metrics)
[2:40 PM] beta_helix: @HuubR Interestingly, Foldit players have helped the Rosetta community improve its energy function (particularly for protein design). One current example is: https://fold.it/portal/node/2010013
Join the author list on an upcoming research paper
Join the author list on an upcoming research paper
[2:41 PM] beta_helix: But even going back to the earlier days of protein design, there were some very big loopholes in the energy function that Foldit players uncovered.
[2:42 PM] beta_helix: Off the top of my head, the diels-alderase Nature Biotech paper (http://www.cis.umassd.edu/~fkhatib/Papers/NatureBiotech.pdf) had a crazy case:
[2:42 PM] pc: Yes, rosetta is for only one protein if I understand. So, without objectives, in design puzzles, when a recipe try to find correct AA between our protein and target, it is like it search AA between 2 Helixies of the same protein.
[2:43 PM] beta_helix: The helix that came back from Foldit had a ton of TRP residues in a row, one after the other, because the energy function rewarded you for residue-residue contacts.
[2:43 PM] pc: BUNS are good to resolve that problem, but lot of players minimise contact with target (so less buried AA).(edited)
[2:44 PM] beta_helix: It revealed many flaws with Rosetta at the time. The same happened when we introduced Foldit symmetry: for some reason Foldit players were trying out things that the automated Rosetta algorithm would never do!
[2:45 PM] HuubR: I have really no idea how the scoring works, but is it possible that some AAs have an intrinsically higher score than others?
[2:45 PM] beta_helix: Pi-helices are another great example. Rosetta never tried breaking an alpha-helix into a pi-helix... but Foldit players did for sure, and that uncovered a bug that had been in the code for years!
[2:45 PM] beta_helix: @pc how is BUNS working for you so far?
[2:47 PM] beta_helix: @HuubR yes, there were definitely many artifacts in there. It's worth remembering that this energy function was initially based on the know proteins that had been deposited in the PDB. Design throws that right out the window!
[2:48 PM] HuubR: That is exactly my point. Design and prediction are completely different concepts
[2:48 PM] beta_helix: Proof: left-handed helices used to be "impossible" then the Baker Lab made one: https://www.rcsb.org/structure/5KX0.
[2:48 PM] beta_helix: I completely agree with you, HuubR.
[2:48 PM] pc: BUNS is a score that is nice to force players or recipes for making strong bouds with targets. But there is a other metric missing. Because lot of players avoid contact with target to reduce BUNS, and it gives lot if points.
[2:49 PM] beta_helix: That is true, pc... and this is the balance we need to find:
[2:50 PM] beta_helix: providing you with the metrics that we use "after the fact" to check the validity of your models... but not giving you required metrics that slow your gameplay to a halt.(edited)
[2:51 PM] pc: maybe we need a metric that give points when we have the orange part (the core existance objective), near the target (and not only with our protein)
[2:52 PM] pc: there is no Shape Complementarity metric eigther, and players make a lot of voids too in hight score solutions(edited)
[2:52 PM] beta_helix: @HuubR The one thing I learned about proteins when I was in grad school is that "there are exceptions to every rule". When I started: knotted proteins were believed to be impossible (and any reported knots were errors or mistakes). If you submitted a knotted model in CASP, it was immediately discarded. Then a bunch of deeply knotted proteins were discovered and deposited in the PDB... and at the next CASP one of the targets had a knot!
[2:53 PM] alcor29: Re SC and rules. Greg Bowman's work at the U of Washingotn, MO seems to show that the covid19 spike acts like a jaw which closes in on its target. In such a case might designing something which blocks that action work even though it has poor shape complimentarity?
[2:53 PM] brunokestemont: IMAGE: http://fold.it/portal/files/chatimg/irc_447652_1595019200.png
[2:53 PM] pc: interesting alcor29 ^^
[2:54 PM] beta_helix: @pc Great points... and indeed a Shape Complementarity is essential
[2:55 PM] beta_helix: @alcor29 Thanks! Can you send me Greg's work? I'll share it with the rest of the team.
[2:55 PM] alcor29: I'll see if I can find it.
[2:56 PM] beta_helix: My opinion w.r.t covid is that we need to try to tackle this problem from all possible angles, so any promising leads are worth pursuing!
[2:56 PM] beta_helix: Cheers, alcor29
[2:57 PM] Susume: what other takeaways did you have from the conference, beta?
[2:58 PM] pc: To try something very different, maybe we need a simulmation tool. Because we never know if something too different will work. And to make points, we often just make a tripple helix
[2:59 PM] pc: objective are usefull to make limitations too. It is true when a laboratory can't make too big proteins for exemple
[3:00 PM] beta_helix: I think the session was quite eye-opening for the computational biology community. I know they've all heard of Foldit, and maybe a few of the other games there, but to see and hear how successful these various projects have been (and how there are all still going on strong) lead to many positive comments (from regular conference attendees) at the end of the day.
[3:00 PM] pc: But too much limitation can limit creativity sometime too (it is difficult I know ^^)
[3:00 PM] beta_helix: Indeed, it's a fine line and a difficult balance to find, @pc
[3:01 PM] lociOiling: @beta_helix will there be a YouTube of your talk and Seth's?(edited)
[3:01 PM] beta_helix: Great question! Yes for sure.
[3:01 PM] beta_helix: and the organizer's hope was to post all the talks online.
[3:02 PM] lociOiling: we will await...
[3:02 PM] brunokestemont IMAGE: http://fold.it/portal/files/chatimg/irc_447652_1595019739.png
[3:02 PM] beta_helix: @Susume I think one thing I learned after reflecting a bit about the session was how it's unrealistic to expect all these games to have thousands of active players.
[3:03 PM] beta_helix: All of these projects reported ~50-200 players at a given time... so that was nice to hear.
[3:04 PM] alcor29: The link to Bowman's demo on Covid 19:
[3:04 PM] alcor29: https://medicine.wustl.edu/news/foldinghomes-fight-against-covid-19-enlists-big-tech-gamers-pro-soccer/
Washington University School of Medicine in St. Louis
Julia Evangelou Strait
Folding@home’s fight against COVID-19 enlists big tech, gamers, pro...
Over 4 million computers worldwide aiding coronavirus research
[3:04 PM] beta_helix: Awesome... thanks
[3:04 PM] beta_helix: Oh, this is Folding@home! Great.
[3:05 PM] clark92: Hi beta_helix
[3:05 PM] beta_helix: Hi Clark92
[3:05 PM] Susume: I'm glad we got some cred with the mainstream bioinformatics folks
[3:06 PM] beta_helix: For sure
[3:06 PM] lociOiling: (Clark92 started in February, and had a 1st place on the last puzzle....)
[3:06 PM] beta_helix: Congrats!
[3:06 PM] beta_helix: That is awesome
[3:06 PM] beta_helix: I generally get last place on all of them
[3:07 PM] clark92: The link above says there are over 4 million computers, why can't we make them become folders?
[3:07 PM] beta_helix: Clark92, may I ask how you find out about Foldit?
[3:07 PM] beta_helix: Great question, Clark92!
[3:07 PM] Susume: I wonder if it would be productive to have an online meeting of players from all the games
[3:08 PM] beta_helix: Funny story: when Foldit started we got a ton of players that came from Rosetta@home (since that was easy advertising).
[3:08 PM] beta_helix: Most of them tried the game as said "this is way too hard" and went back to donating their CPU hours(edited)
[3:09 PM] clark92: Thanks for the compliment; Foldit went viral on Reddit. That's how I found out about it.
[3:09 PM] beta_helix: Some of those people are still playing Foldit though
[3:09 PM] beta_helix: ahh... gotta love Reddit!
[3:10 PM] beta_helix: @Susume that is a great suggestion!
[3:10 PM] Susume: maybe when the videos of the talks from your session come out, we could have some kind of online conversation (even if it is threaded forum rather than real time) between players from the games
[3:10 PM] beta_helix: @Josh has organized meetings with the devs from EteRNA and Eyewire so far... but that is a great idea!
[3:11 PM] beta_helix: I will bring that brilliant idea up to the head of the session (the creator of Phylo)
[3:11 PM] Susume: actually we could probably host it here on the discord
[3:11 PM] beta_helix: For sure! Discord would be perfect
[3:12 PM] beta_helix: I know the Stall Catchers group offered their platform to host all the videos already as well
[3:12 PM] beta_helix: Well thank you all again for swinging by Foldit Office Hours!

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hours 7/30/20- led by Jflat06

[12:59 PM] jflat06: Hey all, we can go ahead and get started
[1:01 PM] jflat06: I don't have a particular focus for this, so we can talk about pretty much anything to do with Foldit development
[1:01 PM] jeff101: hi jeff
[1:01 PM] jflat06: Hello!
[1:01 PM] jeff101: any new ED tools in the works?
[1:02 PM] jflat06: I believe we have recently put out a few improvements for ED. We are also having internal talks (no development yet) about some other improvements.
[1:02 PM] jeff101: what sort of puzzles do you expect to post for the next few weeks?
[1:03 PM] jflat06: The puzzle posting isn't really my area of expertise, but I think we are trying to push for the next round of BUNS filters, using the new devprev which (hopefully) fixes any remaining issues with those
[1:03 PM] nspc:: the coronavirus with new reaction design tool ^^
[1:05 PM] jflat06: We have been holding off on the science side of things for a bit because we were seeing a lot of reports of crashing with the previous devprev, so we haven't been able to use the new filters.
[1:05 PM] nspc:: or maybe adding new metrics for design puzzle ^^
[1:05 PM] jflat06:Yeah, we are definitely working on new metrics (including the BUNS filter)
[1:06 PM] jflat06: we have more metrics in the pipeline, too, but they are very slow, so they will require a rethinking of how we use them to help you fold
[1:08 PM] malphis: h @Susume and I are still experiencing remix crashes in the new devprev on symmetry puzzles. It is a little better than before, but definitely still there.
[1:09 PM] pc: some low computation metrics can be usefull to check if we are in a good way. A player created a DDG recipe this week. This kind of tool can be very usefull in cpp, and usable in lua
[1:12 PM] jflat06: hopefully the metrics we give you will be much faster than the ones people code up in LUA (and hopefully more accurate, too)
[1:12 PM] pc: cool
[1:13 PM] jflat06: The remix crashes theoretically shouldn't be happening, since we essentially undid the changes that were in the previous devprev'
[1:14 PM] jflat06: It's possible our "undo'ing" wasn't completely clean, we can look into it
[1:14 PM] jeff101: please do
[1:15 PM] pc: after a round, I have often 20 saved solutions. I just select the top score of each alternative solutions. but with a low computation tool that give a more accurate score, I can do a better selection for scientist share
[1:15 PM] jeff101: could you raise the # of shares to scientist to say 10 per puzzle?
[1:16 PM] jflat06: We should be able to do that - from a talk we had in a meeting the other day, it sounds like if you just overwrite some of existing scientist shares, we'll still get them all
[1:16 PM] jeff101: in the ligand puzzle 1855, having more shares to scientists would been helpful
[1:17 PM] jflat06: But I think it should be really easy to change the number of shares
[1:17 PM] jeff101: in those sketchbook puzzles with limited # of moves, having more shares to scientists makes sense
[1:18 PM] jflat06: Yeah definitely
[1:18 PM] jflat06: (remember that we also still get all of your solutions, even if you don't explicitly share them)
[1:19 PM] pc: mabe solutions we save in local can be get in priority too
[1:19 PM] jeff101: I often count on that, but I was told that only 5 share w/scientists + best solo + best evo are actively looked at by the scientists ... the rest are like backups for global automated analysis
[1:20 PM] jflat06: From the sound of it at the meeting, it sounds like we still keep around any of the 'replaced' ones, so we actually do look at them all
[1:21 PM] jflat06: I'm taking a look at the client code right now to see if the 5-limit is coded in there, or whether it is completely server side
[1:21 PM] jflat06: I'm pretty sure it's server side, in which case I can easily tweak it without needing a client change
[1:23 PM] pc: some players use external tool to make a protein analisis in design puzzle. Maybe some can be in game
[1:23 PM] jflat06: That's actually the main focus of our development plans for design puzzles right now
[1:24 PM] pc: we need to experiment too. Sometime I ask me question "is it stable," "is the protein move or stay stick?"
[1:25 PM] pc: I know there is no physic simulation in game, but sometime it can be usefull to experiment and discover and try something new
[1:25 PM] pc: For beginers, it is often better to make a safe triple helix because we know it works, but we dont realy see why at begin.
[1:26 PM] HuubR: nspc, you sometimes speak about DDG. Do you then just move the monomer away and check how much the score drops, or is there more to it than that?
[1:27 PM] pc: yes
[1:27 PM] pc: often, the score stay high
[1:27 PM] pc: for some bad solutions with buns, score can be better too
[1:28 PM] pc: this is one of the hack in puzzle design : some top score solutions are very far and not connected to virus
[1:29 PM] HuubR: Would there be any way in which we can make DDG count for binder designs? Or is that just what the devs are working on?
[1:29 PM] pc: I know that, so I try to stay in contact with virus and try to make no additional buns
[1:29 PM] pc: we need first some metrics that fix some score hacks ^^
[1:30 PM] HuubR What exactly do you mean by score hacks?
[1:30 PM] pc::
[1:30 PM] pc: this ^^
[1:30 PM] jflat06: Ok, I've increased the number of scientist share slots to 10
[1:31 PM] pc: cool
[1:31 PM] malphis: I don't think hack is the right word, it's just what foldit and the script we have tend to do.
[1:31 PM] jeff101: :)
[1:31 PM] HuubR: Shall we try it now? :D
[1:32 PM] jflat06: Go ahead! From what I can tell, there shouldn't be a problem
[1:32 PM] MikeCassidy: I am old 'hack' means to me: 'Quick and dirt'; UNIX was originally Quick and Dirty
[1:33 PM] pc: sorry I am french, maybe i dont use the better words ^^
[1:33 PM] MikeCassidy: I always wondered how it got hijack to mean braek ing into computer systems
[1:34 PM] jflat06: That one I think is pretty close to the actual definition
[1:34 PM] malphis: It's just something that isn't restricted by the objectives and scoring functions. In my experience, it is difficult to make bonds at all.
[1:34 PM] jeff101: I use bands to force bonds to form
[1:35 PM] jeff101: h-bonds and disulfides h have "ideal" distances and directions, so often I need 2 bands to form 1 hbond and 3 bands to form 1 s-s bond
[1:36 PM] jflat06: I wonder if we can make a special kind of rubber band that includes constraints on h the distance AND directions...
[1:37 PM] HuubR: When you use bands to create H-bonds, does it help to do that in Stick view, where you can attach the band to the individual atoms?
[1:37 PM] jeff101: the web page for the recipe bandsome gives more details
[1:37 PM] jeff101: stick view and cpk coloring helps
[1:37 PM] pc: sometime I create a triple helix with little hydrophilic sidechains outside, and wiggle in a zone. I test multiple zones and manualy change some sidechain. I mutate, try again.. and sometime it found some good bouds.
[1:37 PM] jeff101: bandsome asks for specific atom #'s to connect
[1:38 PM] HuubR: When I then switch back to Cartoon, the band seems to shift. Is that really so, or is it just the visualisation that changes?
[1:38 PM] jflat06: it should just be a visual change
[1:38 PM] jeff101: I think the visualization just changes
[1:39 PM] malphis: maybe I should have qualified that with as little force as possible. I do place the monomer at what I think is a good docking spot, but then just vary CI, wsm.
[1:39 PM] jflat06: the bands dont even know about the visual representation of the protein - they are using a different complete "full-atom" version of the protein model
[1:39 PM] jeff101: sometimes changing cartoon/stick etc helps see the desired bonds ... often the bands hide the desired bonds
[1:40 PM] jflat06: yeah, we can probably do some work to increase clarity for these types of situations
[1:40 PM] jeff101: if you're going to make a new kind of band, please make a band that is 1-directional
[1:41 PM] jeff101: like a bumper on a car (it only repels when its distance is below a certain cutoff)
[1:41 PM] jeff101: or a spring attached to a long string (it only contracts when it is stretched beyond a certain distance)
[1:42 PM] jflat06: The repulsion should be handled automatically by the fa_rep term in the scorefunction
[1:42 PM] HuubR: Can you push things apart with a band?
[1:42 PM] jeff101: yes
[1:42 PM] jflat06: yeah
[1:42 PM] jflat06: a band is just a "constraint" - it tries to make a value be another value. So if the desired value is greater, then it will "push"
[1:42 PM] jeff101: https://fold.it/portal/node/996372
[1:43 PM] jeff101: 1-directional bands ^^
[1:44 PM] jeff101: foldit bands right now are 2-directional: they contract if stretched too far and they repel if their lengths get small
[1:44 PM] jflat06: I think rosetta in general can use pretty much whatever function you want underneath for determining the constraint behavior
[1:44 PM] jeff101: yes, but we can't code rosetta in LUA
[1:44 PM] jflat06: I'm not sure how hard or easy it would be to have multiple options available in the GUI/LUA
[1:44 PM] jeff101: the FOldit devs could give us more tools
[1:45 PM] jeff101: https://fold.it/portal/node/996372#comment-38712
[1:45 PM] jeff101: above shows some rosetta pages about constraints
[1:45 PM] jflat06: Would be a question for the more rosetta-fluent of our developers. I can ask around
[1:46 PM] jeff101: I think 1-way bands can already be done directly in rosetta
[1:47 PM] BletchleyPark: Is there a programmatic interface for pushpins ?
[1:48 PM] jflat06: The main issue in Foldit would be that we don't currently track anything other than the fact that there is a band, so we'd have to restructure the internal state of our protein model as well as save formats, etc. Depending on how engrained the idea that "a band is just a band" is, it could be easy, or it could be hard.
[1:48 PM] jeff101: giving us view options like show bands / hide bands would help us see if our bands have made the bonds we want. transparent or translucent bands would help in the same way
[1:48 PM] jflat06: @BP I believe that was either added recently, or else is being added soon
[1:48 PM] BletchleyPark: Ok, thank you, how would I know / how can I find out ?
[1:48 PM] Xartos: jeff101: you can simulate 1 way bands with selecting only the part that you want to move ?! or am i wrong?
[1:49 PM] jflat06: If it isn't in the release notes, then it's likely still in the works
[1:49 PM] jflat06: from what I can recall, I think we haven't pushed that one out yet
[1:49 PM] BletchleyPark: How do I get the release notes ?
[1:50 PM] jflat06: News posts are the most reliable source. The new site will have them automatically attached to the releases, so it will be much more organized
[1:51 PM] BletchleyPark: ok, thank you ! I'll be afk in a few minutes, have a great day.
[1:57 PM] jeff101: one thing I've ask for in the past is a version of the Nelder-Meade Simplex Direct Search method implemented in FOldit
[1:58 PM] jeff101: it seems like something that could be coded in LUA, but if it were a built-in FOldit LUA function, that would be great
[1:59 PM] jflat06: I'm not well versed on that, but I'd be curious to see if anyone's put it into Rosetta already
[2:00 PM] jeff101: the post below talks about using it to improve the Align Protein to Density button for ED puzzles
[2:00 PM] jeff101: https://fold.it/portal/node/993959#comment-32465
[2:01 PM] jflat06: The gradient descent algorithms that the minimizer uses are pretty good at what they do. The main thing that looks interesting about the Nelder-Mead is that it doesn't require derivatives, which could be useful for things like our Filters that aren't currently included in minimization (since gradient descent requires derivatives)
[2:01 PM] jeff101: right. NM doesn't need derivatives.
[2:02 PM] jeff101: if NM were built into FOldit, you could use it with xyz coordinates for the atoms to make the Align Protein to Denisty Button work better
[2:03 PM] jeff101: it would be harder for a player to code as a recipe because we don't have access to all the coordinates and density data we would need
[2:03 PM] jflat06: I think what you'd want to do is just set up a 6DOF space with the location/orientation of the entire model and apply NM to that
[2:05 PM] jeff101: I've seen NM work well in optimization problems up to about 20 variables
[2:05 PM] jflat06: Yeah, it might work for alignment
[2:06 PM] jeff101: I don't know how many variables will make it perform worse
[2:06 PM] jeff101: generally more variables takes longer
[2:06 PM] jflat06: the actual optimization space of general folding is significantly more complex, though. thousands of degrees of freedom.
[2:07 PM] jflat06: The main problem with the align-to-density tool is that a lot of proteins (especially helical bundles) tend to look pretty similar even when rotated about their axis
[2:07 PM] jeff101: but for taking the protein as a rigid body and finding the best position and orientation for it to match the ED, you only need xyz for translation/position, and 3 euler angles for direction
[2:07 PM] jflat06: right
[2:08 PM] jflat06: it's a 6DOF space, so it's much more manageable
[2:15 PM] jflat06: Thanks all for showing up! - I am going to go grab some lunch now.
[2:15 PM] jeff101: thanks for coming
[2:15 PM] jeff101: these meeting are helpful
[2:16 PM] jmbrownlee333: Have a nice lunch. I second what jeff says.
[2:16 PM] HuubR: Yes, it was an interesting hour!

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hours 8/14/20- led by Sciren and rmoretti

[1:04 PM] sciren: Hello everyone! I hope everyone is having a great Friday so far. As @agcohn821 mentioned I am a developer for Foldit and have been working on Ligand based tool sets for the game.
[1:04 PM] donuts554: hello how are you?
[1:05 PM] sciren: I've never had a virtual office before, but then again I've also never had my own office so I think this works well!
[1:06 PM] sciren: I am doing well Donuts544. Its been a little rainy lately, but I like that. How are you?
[1:07 PM] donuts554: I am good, thanks for asking!
[1:07 PM] donuts554: I have a question
[1:07 PM] sciren: Sure thing!
[1:08 PM] donuts554: Why is there a limited number of choices in each column of the Reaction Design tool?
[1:10 PM] sciren: Let me make sure I understand your question. Are you talking about the "reagent" choices for the tool?
[1:11 PM] donuts554: Yes the reagent reactant choices
[1:15 PM] sciren: Perfect. Each puzzle that we release with the Reaction Design tool will have a varying number of reactant choices. For the latest puzzle we had a specific series of designs that could be made to suit the problem at hand. This will not always be the case. The tool is designed to only display 10 choices at a time, but it can pull from a much larger dataset. When this happens, you will still only have access to a those 10 choices, but there is other functionality to propagate other reactant choices.
[1:15 PM] jeff101: @sciren: have you read any of the feedbacks below?
[1:15 PM] jeff101: https://fold.it/portal/node/2009896
[1:15 PM] jeff101: https://fold.it/portal/node/2009887
[1:16 PM] sciren: I have indeed jeff101:. I actually have them bookmarked and am using them to update the tool.
[1:17 PM] pc: The main problem I had when I used liga the tool is : When I want to change a part of the molecule, it moved all or changed part I choosed. I needed somethink like protein design : base molecule that not move (like a backbone that not move duruing edition), and I can add a new part with a contextual menu (like I choose a new sidechain or add a new backbone part). It is important to keep the other parts in same position to keep the bouds with target.
[1:17 PM] jeff101: that's good. what things have you been working on?
[1:17 PM] sciren: For me, I get to see the inner working of the tool and have stared at it for many many hours. So it is was really amazing to have all of you look at it with fresh eyes so that I could see areas that needed improving.
[1:19 PM] sciren: PC are you saying that what you were wanting was to change a portion of the ligand at a time?
[1:19 PM] jeff101: I like 06pc's idea above. Perhaps make something like the Blueprint Tool with Building Blocks
[1:20 PM] jeff101: or the mutate buttons
[1:20 PM] pc: Yes maybe add parts on the molecule with only contextual menu for the exreminity with selected
[1:21 PM] jeff101: but I guess connectivity is different for small ligands ... they aren't just chains of amino acids ... they can have branches and rings too
[1:22 PM] jeff101: more like a 3-d object than a 1-d object
[1:22 PM] rmoretti: One limitation of the Reaction Design tool is that it's designed for compound libraries where you have a sort of fixed enumeration of reagents. We're hoping to keep the tool close to that approach such that the molecules we get out of it can be synthesized by those techniques. (Which are distinct from that sort of arbitrary modification.)
[1:22 PM] sciren: jeff101: It never occurred to me that having a number or some other sort of representation on the reactant choices would be something that would be beneficial for collaboration. Also adding additional color dependent on which reactant column is chosen was a great idea as well. These are two of the addition/updates that I am working on.
[1:23 PM] rmoretti: That said, we do have another person who is looking at different (better) ways of lining up the old and new molecules such that they "match" better and more directly.
[1:24 PM] rmoretti: (Also, the concept of adding other tools which will allow that sort of targeted modification is something that's on the todo list.)
[1:25 PM] jeff101: I've been playing with 1855 (the Y1 receptor ligand design puzzle) since it ended. It would help a lot to have a tool that counts the # of h-bonds the ligand makes to the protein
[1:25 PM] Josh: I wonder if that's something a recipe could do?
[1:26 PM] sciren: That's a good point Josh(edited)
[1:26 PM] pc: Maybe we can start with a complex base molecule part, and add more simple after with a contextual menu. But yes, it is not a simple chain. For complex branchs, contextual menu or 3d visualisation still possible I think
[1:26 PM] jeff101: it would also help to have a function like GetAtom() to list the atom type (N H O C etc) for atoms #'s on the ligand or other sidechains
[1:26 PM] Susume: rmoretti: when you say compound libraries, do you mean we are choosing from a list of reagents that scientists already know how to make in the lab?
[1:28 PM] rmoretti: Susume - Yes, more or less. There's particular reactions the organic chemists know how to run (across the top) and then there are reagents they have access to (in the columns) and running the reaction is as "simple" as picking the reagents to use in the reactions they can run.
[1:29 PM] LociOilingIRC: @Josh, a recipe can't count ligand bonds, since the chemistry of the ligand is a black box - can't tell C from O or N
[1:29 PM] rmoretti: Different projects will have different sets of reactions and reagents the collaborators will be able to work with.
[1:29 PM] donuts554: From what jeff said, I think the reaction design tool should be more about modifying the bonds for each and every heavy atom
[1:30 PM] jeff101: on my screen right now, I see 3 hbonds giving a bonding score of 14.4-15.1 (it varies) for the ligand in 1855
[1:31 PM] donuts554: Such that there are internal restrictions as to which bonds can form and which bonds can't form/ not allowed to form
[1:32 PM] donuts554: Why isn't this the case?
[1:32 PM] sciren: So that is a different design process donuts554. For this tool, as rmoretti has mentioned, the idea is be able to create ligands that are either readily reproduceable, or at least follow known methods of synthetic production.(edited)
[1:32 PM] jeff101: now I see 18.4 for 3 hbonds
[1:33 PM] Susume: @LociOiling would it useful (once the tool stabilizes enough to add lua functions for it) to be able to ask what element a given atom of the ligand is?
[1:34 PM] sciren: jeff101: I'm not certain about the varying bonding score. It is something that I can look into though.
[1:34 PM] jeff101: @Susume I would say definitely. It would help for amino acids too, like how to tell which type of histidine is present
[1:35 PM] robgee: Just label those reagents and i'll be happy :)
[1:36 PM] rmoretti:: @LociOiling What's the process by which a recipie can get the info for an amino acid? If that consults a Lua call, there's theoretically no reason why that shouldn't also work for a ligand. (If it's using an internal lookup table in the recipie, then it wouldn't be, though I'm guessing it would be possible to convert the table to a lua call, if such a table is generally useful for recipies.)
[1:37 PM] sciren: robgee, well then I hope you will be happen when the tool gets updated!
[1:37 PM] donuts554: Yes sciren, but I mean that following the known methods of synthetic ligand reproduction, there should be a list of available "functional groups" that can be bonded to each heavy atom
[1:38 PM] jeff101: for amino acids, you can use stick view and cpk with a recipe like bandsome to tell which atoms are which. then you make a table, like brow and perhaps others have made
[1:39 PM] donuts554: And there can be some sort of restriction that follows the known methods of synthetic ligand reproduction as to which functional groups can be --added/removed-- to each heavy atom
[1:39 PM] jeff101: but amino acids are generally the same from puzzle to puzzle. ligand puzzle reactants seem to vary more, and how they fit together and get numbered is mysterious
[1:41 PM] Susume: maybe @Josh and @sciren could work together to give us lua better visibility of atoms in h proteins and small molecules - right now I think atom number is the only way we have to access individual atoms, and as jeff says we have to back into knowledge about the atoms from there
[1:42 PM] sciren: I'm not saying that that isn't a possibility. However, currently to be able to design reactions that are reproduceable in the lab requires a lot of chemical knowledge.(edited)
[1:44 PM] Susume: it kinda makes sense to let us demonstrate we can do something useful with a limited set of legos before letting us design our own legos (which would require coding in the rules for how to design valid legos)
[1:45 PM] sciren: That's actually a really great analogy Susume!
[1:45 PM] jeff101: so far in these puzzles, if you pick a certain set of reactants, do you always get the same ligand product?
[1:46 PM] jeff101: I know some things in organic chemistry have probabilities to form different products ... like adding functional groups to rings ..you worry about ortho para and meta (I think).
[1:46 PM] rmoretti: The original ligand design tool allowed much more flexibility in how ligands were constructed. The issue there was that Foldit players took full advantage of the flexibility to create molecules which were ... interesting. That's our (the developers') fault there, as we didn't put in rules which limited things to be reasonable. The problem is that coming up with such rules was harder than we anticipated, so we tried a different tactic with the Reaction Design tool.
[1:46 PM] Susume: I think one column was for chirality - different shapes that can be made from the same reactants?
[1:47 PM] donuts554: Because there is a wide variety of known organic chemical reactions possible, why is there a limited number of organic chemical reactions in the top row?
[1:48 PM] rmoretti: Susume - Right. One of the reagent choices for the first puzzle was either a "D" or an "L" arginine, which were two options in how the library we were targeting was constructed.
[1:48 PM] sciren: jeff101: if you choose the same set of reactants, you will get the same products
[1:50 PM] sciren: donuts544 we were only looking at those particular reaction types, which will be the case for all of the puzzles. Though for puzzles that we are using a much larger chemical library, those reaction types will increase.
[1:51 PM] pc: Yes I want to play lego ^^
[1:51 PM] sciren: Same pc. Same.
[1:52 PM] donuts554: Based on what rmoretti: said about limiting ligands to be reaosnable,
[1:53 PM] donuts554: I think I found a list of rules that have already come up in organic chemical reactions
[1:53 PM] donuts554: And have been put into an online application
[1:54 PM] donuts554: alchem.ie/mechanisms
[1:55 PM] sciren: Where was this when I was taking organic Chemistry??
[1:56 PM] donuts554: Is there any constraint in the Rosetta software that doesn't allow for this, or is this technique as mentioned above possible?
[1:57 PM] donuts554: I also think that this techinique has the portential of being used in FOldit Education mode to teach chemistry as well as to design ligands at the same time
[1:57 PM] donuts554: It sounds very ergonomical
[1:57 PM] jeff101: if you let us pick which item to use in each column using LUA, we can make recipes that automatically go through all the combinations ... like a way to screen the ligands
[1:58 PM] donuts554: and efficient
[1:58 PM] sciren: One of the things that rmoretti also mentioned was that the implementation of these rules proved much more difficult to implement than originally thought. That is reason behind the reaction based approach.
[1:59 PM] donuts554: oh ok, I just thought that a functional-group based approach or a electron-based approach would work well
[1:59 PM] sciren: That is something we can definitely take that into consideration jeff101.
[2:01 PM] donuts554: One thing I like about the reaction design tool is that when it resets your ligand to a default position when you choose new reagents,
[2:02 PM] donuts554: It seems that it eliminates the possibility where there the ligand is inimpossible conformation &/or position
[2:02 PM] jeff101: does that mean if you use the same set of reagents again, you will get the same product formed in the exact same position with respect to the protein and so get the same Foldit score?
[2:03 PM] donuts554: for me, yes
[2:03 PM] sciren: I want to take a moment and thank all of you. Not only for all of your hard work on these puzzles, but also for your feedback. This is invaluable to designing and improving toolsets for all of you. I have also very much enjoyed getting to watch this amazing community of Citizen Scientist do such amazing science!
[2:04 PM] donuts554: You are welcome!
[2:04 PM] robgee: Cheers sciren
[2:04 PM] jeff101: thanks sciren and rmoretti for coming

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hours 8/27/20- led by Milkshakeiii

[2:34 PM] milkshakeiii: Hello I'm milkshake and I'm hosting this week's office hours. I can talk about foldit performance and crashing, a topic which I know many are interested in, haha.
[2:36 PM] skippysk8s:k8s: What can we do to fix dremix on the trimers. A lot of us would like to use it for early game, but it always crashes
[2:37 PM] milkshakeiii: We believe there is a crash related to remix itself
[2:38 PM] milkshakeiii: There are a lot of crashes caused by bugs in the code
[2:39 PM] milkshakeiii: Haha
[2:39 PM] susume: have you been able to reproduce a crash using remix?
[2:40 PM] milkshakeiii: Sort of, I think I am starting to get a lead on it
[2:40 PM] milkshakeiii: The reproduction steps for crashes that you have sent us have been really helpful Susume
[2:40 PM] susume: thx, I love to break things
[2:40 PM] milkshakeiii: Haha
[2:42 PM] pc:When we send log after a crash. it looks there is often net very usefull log information. Maybe we need more log, or enable a "more log option" for user who want help?
[2:43 PM] pc: The log file when we restart foldit is cleared by the new one. Maybe we can keep the old after a crash (we can detect foldit didnt closed normaly). and maybe auto send a zip with crash report (with user activated this option ?)
[2:45 PM] milkshakeiii: Unfortunately backtraces get lost on segfault, which means for many of the crashes the log file just terminates when the program crashes
[2:46 PM] milkshakeiii: We do actually get automated uploading of log files, which is nice though, so in many cases you don't actually have to do anything and we will get a report
[2:46 PM] pc:oh ok thanks
[2:47 PM] jeff101:Hi Milkshake,
[2:48 PM] jeff101:I even found Rosetta commands that could be used to implement them.
[2:48 PM] pc: for the last metrics, there needed many software update to have something working. It is strange that is was not tested enough, or there is difficulty to know if something work before ? is it because you need more end game protein to test, or something else ?(edited)
[2:49 PM] milkshakeiii: You mean the new binder metrics like DDG and such, right?
[2:49 PM] pc: yes. but now it works ^^
[2:50 PM] milkshakeiii: Yeah there were a lot of devprev pushes for that
[2:50 PM] milkshakeiii: It was a combination of things
[2:52 PM] pc: maybe there is something to improve in production process. (at my work we have a tester team, its help of course ^^)(edited)
[2:53 PM] jeff101:https://fold.it/portal/node/996372
[2:53 PM] jeff101:above is one feedback about 1-way bands. it lists the rosetta code.
[2:54 PM] jeff101:https://fold.it/portal/node/996372#comment-38712
[2:54 PM] milkshakeiii: 1-way bands, interesting
[2:54 PM] devjosh: having more testers would be great if we had the money for it haha
[2:55 PM] pc: yes ^^
[2:58 PM] jeff101:Milkshake, what aspects of Foldit have you worked on? Does you Math background ever come in handy?
[2:58 PM] pc: for new metrics, so you work on something that compute faster ?
[3:00 PM] milkshakeiii: I started earlier this year and I've worked on small UI changes as well as crash fixes and improving the performance of rubberbands, and some new features for new objectives
[3:01 PM] milkshakeiii: I haven't gotten the opportunity to apply much math to foldit yet sadly but I have gotten to learn about some interesting techniques used in Rosetta for surface area calculations for example
[3:01 PM] MikeCassidytoo: New objectives other than DDG, SASA Score and Shape Comp?
[3:01 PM] jeff101:one way to speed programs is to look for multiplications by zero and rearrange loops to avoid multipling by zero
[3:02 PM] pc: There is lot of same recompute maybe too
[3:03 PM] milkshakeiii: yeah I focused a lot on reducing recomputes during my first couple months
[3:03 PM] pc: cool
[3:03 PM] milkshakeiii: I did manage to eliminate some recomputation related to rubber bands and undoing
[3:03 PM] milkshakeiii: Not sure if anyone noticed though, haha
[3:03 PM] jeff101: the time saved probably got used by another feature
[3:04 PM] skippysk8s:k8s maybe the rubber bands he he
[3:04 PM] jeff101:if you understand the math behind something, you can reformulate it to be more efficient
[3:05 PM] pc: do you keep all solutions database of each puzzle round?
[3:05 PM] jeff101:one professor joked about someone not realizing they could use a sine function for what looked like a complicated program
[3:06 PM] milkshakeiii:I haven't actually touched the solutions database yet, I know that we definitely keep the ones that people click "submit to scientist" on, and even express them in the lab sometimes, that's bkoep's area
[3:07 PM] pc: do you keep the all other solutionsnot just shared to scientist?
[3:07 PM] Formula350: Yea Skippy, band creation in Recipes really are a major processing hog and I could see people not being able to notice any gain, or gain elsewhere, due to that.
[3:07 PM] pc: it is because that can be usefull in deep learning to compute metrics
[3:07 PM] Dudit: faster new metrics using GPU ?
[3:08 PM] milkshakeiii: I haven't looked at GPU yet, have been looking at multithreading
[3:08 PM] Formula350: I also wonder then, if the major delay while tools are running (wiggle specifically), and trying to create bands where it ends up having a delay on mouse click release, is related to refactoring the bands code? :S(edited)
[3:08 PM] pc: with a large database with can apply a fast compute using simple game elements than void, position.. and compare with a real metric, and find the correspondance(edited)
[3:09 PM] milkshakeiii: formula350, I'm glad you noticed the delay on mouse click release
[3:09 PM] milkshakeiii: that's exactly what I tried to get rid of
[3:10 PM] Formula350: Oh, it actually cropped up. Was the same release where the double-click to freeze on Objectives puzzles was fixed. If that helps you narrow it down. (So, roughly 2mo ago)
[3:11 PM]jeff101: do you have a debugging tool that lists the fraction of compute time spent on each line of code. that can be very helpful
[3:11 PM] milkshakeiii: i'll look into it, ideally adding a rubber band should not cause a noticeable delay
[3:12 PM] milkshakeiii: are there any puzzles currently active that you're seeig it on?
[3:12 PM] pc: jeff : there is get date function for that in c++ yes ^^
[3:12 PM] Formula350: I think I linked Josh a bunch of those kind of polling programs back in late-march, Jeff. He passed 'em along to the rest of the team (but as a non-coder, who knows if they were actually usefull or not already known about lol)
[3:12 PM] milkshakeiii: jeff101 yeah we do have that, c++ has a lot of debugging tools which is nice
[3:12 PM] robgee: ollydbg ftw :)
[3:13 PM] Formula350: I'll talk with you about it after your Office Hours, so I don't tie you up with this Bug Talk lol
[3:13 PM] milkshakeiii: roger
[3:14 PM] jeff101:roger roger (as in Star Wars: The Clone Wars series)
[3:14 PM] jeff101:or that movie Airplane?
[3:15 PM] milkshakeiii: lol, I actually love sw the clone wars
[3:15 PM] milkshakeiii: surprised to see it mentioned here haha
[3:15 PM] jeff101:there's supposed to be a new season on Disney+ soon
[3:15 PM] milkshakeiii: that's actually out!
[3:16 PM] milkshakeiii: an epic conclusion with lots of Ahsoka Tano haha
[3:16 PM] milkshakeiii: you should watch it
[3:16 PM] jeff101: gotta have Disney+
[3:17 PM] pc: Do you think we can use some simplier metrics : for exemple just "number of sidechain near target" to have score, instead of real SASA ? or you think it make a real difference to use the real metric?
[3:17 PM] Formula350:And Ahsoka is getting a Live Action appearance in one of SW shows, too
[3:18 PM] pc: a simple metric that increase score with contact with target, avoid the problem that some recipes make the protein far to save some buns for exemple
[3:18 PM] milkshakeiii: these metrics were mostly designed by protein scientists and they are quite advanced from what I understand, if you get a high enough score on those three metrics you can actually be fairly sure you've designed some sort of binder
[3:19 PM] milkshakeiii: i'm not a protein scientist though
[3:19 PM] Dudit: in the latest main Foldit build, the monitor screen did not turn off (even when I set it to turn off after 10 minutes of inactivity)
[3:20 PM] jeff101:maybe a hacked together approximate version f the metrics would give similar values but calculate faster
[3:21 PM] jeff101:like use step functions instead of Gaussians
[3:21 PM] jeff101:or linearize things
[3:21 PM] pc: so, good and fast metrics need scientist and programmer / maths skills in same time.
[3:21 PM] jeff101:Pade Approximation? power series? polynomials?
[3:21 PM] milkshakeiii: i am actually working on something that should make those metrics much less annoying to work with
[3:22 PM] milkshakeiii: at the risk of foreshadowing ha
[3:23 PM] jeff101:multipole expansion? fourier transforms? laplace transforms?
[3:23 PM] Formula350: I personally love their current non-scoring, user-triggered nature ^_^ Alas, I know that won't remain how they'll function lol (which I also understand why they won't)
[3:24 PM] jeff101:Ewald summation?
[3:24 PM] pc: When I play, I somethimes try to ignore the score system, and focus on what happen in reality. but when we use recipes, only score is used for heuristic, and we can be stuck in a bad hightscore solution.
[3:25 PM] Formula350: Time dilation. Einstein-Rosen Bridge. Dodecahedron. SEE Jeff, I can do that too! /sarcasm lol
[3:25 PM] pc: the next puzzle with score in new metrics will help a lot I think ^^
[3:25 PM] milkshakeiii: haha, math name games are always fun
[3:26 PM] jeff101:or for common calculations, make like a graph/table of x and y values and use them instead of the raw functions
[3:26 PM] milkshakeiii: cacheing is indeed a good speedup method
[3:27 PM] Formula350: Yea PC: I hear that! I loaded one of our teams highest score on Corona to see what the Metrics looked like in comparison to my massively poorer scoring solution, and I was surprised that my New Metrics were substantially better <_>
[3:28 PM] pc: you had bas score but new metrics were goods?
[3:28 PM] jeff101:way to go F350!
[3:28 PM] Dudit: is there a minimum system requirement in Foldit for running new metrics?
[3:28 PM] pc: In our better solutions we are very near of the 1500 SASA(edited)
[3:29 PM] Formula350: Wonder if, thanks to the larger L3 cache that CPUs of the last 5yrs have had, that it could somehow be leveraged to speed up Foldit a bit. Maybe store the entire Recipe in the L3 cache? (I'm out of my element here, and just shooting spitballs at the ceiling to see what sticks)
[3:30 PM] jeff101:brainstorming splatter on the walls
[3:31 PM] pc: do you think deep learning can be used to compute faster metrics, using the large database of all previous solutions?
[3:31 PM] milkshakeiii: that sounds a little bit like bitboards, which are also fun speedup techniques
[3:31 PM] Formula350: Dudit, Foldit is a curious beast when it comes to what it can run on, and what it runs faster on. It very much still feels like a 2010 program, and so the better the system you have, reaches its limits for speeding up what we do. (in my experieence, going from a 2015 laptop to my desktop)
[3:32 PM] milkshakeiii: game programming doesn't really work on the level of processor caches thogh
[3:32 PM] pc: Or do you think we can reuse a part of some previous solution,s to help recipe to find the best sidechain for a position
[3:33 PM] Formula350: I personally don't look at Foldit in the "it's a game" sense. I liken it closer to CAD, or Photoshop, or perhaps like Universe Simulator (which is much more borderline "game" but just as much "educational tool" like Foldit)
[3:33 PM] pc: for that I thinked of a feature : In each round we create a database with : some sidechains at a position with a bound with target. And we can use them in some recipes to help find best boud with target(edited)
[3:34 PM] pc: yes fodit is not a game, it is a scientific software, that.. look like a game sometimes
[3:35 PM] milkshakeiii: that's quite true haha
[3:35 PM] Formula350:That's similar to something I'd requested PC:, but actually applies it a bit in a different way. I've wanted a sort of "personal storage" system for portions of Poses, that we can access like Building Blocks, to paste into the game.
[3:36 PM] jeff101:maybe break up the metrics a bit like we vary the wiggle power ... lo wiggle power is faster but doesn't adjust all the bond lengths and angles ... hi wiggle power is slow but varies some bond lengths & angles
[3:36 PM] pc: for my suggestion, the idea is to have a progression in each round. Something we can reuse to have better solutions that work in lab ^^
[3:36 PM] pc: I think in each round end we need a simple "best sasa, best ddg.." score to compare
[3:38 PM] milkshakeiii: that would be useful
[3:38 PM] Dudit: or maybe best total objectives score to compare?
[3:39 PM] Formula350: Maybe being able to see the metrics with a very blurred image of the solution, to not give away details, but still sort of give you an idea of what was needed to attain that (ie, sidechains wouldn't have enough detail to tell which they are). Would still give us feedback, but then still permit design diversity for the science side.
[3:40 PM] milkshakeiii: i think there's a high probability bkoep might post something like that a little later
[3:40 PM] milkshakeiii: but not sure exactly what his plans are
[3:40 PM] Drum: these novice puzzles are actually harder to get a high rank
[3:40 PM] jeff101:regarding calculating the metrics, use cutoffs so that if things are too far apart to give significant scores, give them scores of zero instead of doing the full calculation
[3:41 PM] Formula350: I like that Jeff.
[3:41 PM] skippysk8s: Jeff's suggestion is good. often we build a monomer to get past all the other filters before docking it
[3:42 PM] pc: End round statistics can help us to know what was wrong in last round. In lot of rounds before new metrics, I saw hight score solutions with not a lot of contact with target. With some score détails (like low sasa in most of solutions) we can can understand what we have to do better in next round
[3:42 PM] Formula350: Not just the New Metrics, but the BUNS, too. Yes, for just the reason Skip said. Would let you design further out in space, still have the objectives turned on, but due to distance would not calculate some since it's pointless.
[3:44 PM] Formula350: PC: that's exactly why I liked Skippy's suggestion a couple days ago (I pinged bkoep but didn't hear back), to allow us to load in our personal designs from all past rounds of that puzzle. So we can run the New Metrics on them and see which of them may be viable with tweaks.(edited)
[3:44 PM] pc: yes, the buns number change when I move a very far protein from target
[3:44 PM] pc: I mean, the protein that was already far
[3:46 PM] Formula350: Yea the BUNS filter I personally think, might need its sensitivity dialled back JUST a tiny bit. Being able to wiggle 1 single selected segment and have it cause 4 BUNS on the target is an eyebrow raiser for me. haha
[3:46 PM] jeff101:if several teams contribute to a metric, try to estimate which term will be the largest, calculate that, and leave off the others. this works well if one term is dominant (like 90% of the total)
[3:46 PM] robgee milkshake, do you view the asm when you debug or is that not necessary ?
[3:47 PM] milkshakeiii: gdb is my go-to tool when the simplest methods fail
[3:48 PM] milkshakeiii: viewing compiler output is not good for the brain
[3:49 PM] HuubR About loading previous solutions to check how they score on the new metrics: would it be possible to create a sandbox for that, with all the filters + metrics available?
[3:50 PM] pc:I hope we will have score in new metrics soon. it is realy what its missing to have more chances to have working solution in lab
[3:52 PM] skippysk8s: agreed. One of our team had a nice shape to hook around on a binder. It was a really great shape. Perhaps we can do a contest if we can't get things into the sandbox. Each team can nominate some candidates
[3:52 PM] pc: for you idea huubr, we can create a menu too, accessible everywhere that can run some protein analysis (like metrics).
[3:53 PM] pc: a "protein analisys" menu. So we can open old rounds and run new metrics on them
[3:53 PM] Dudit: are Foldit top solution being used in Rosetta@home ?
[3:53 PM] pc: or of course, if new metrics are accessible in lua, we just have to run a recipe that call one function
[3:54 PM] milkshakeiii: Rosetta@home is used by scientists to design the own "solutions," basically
[3:54 PM] milkshakeiii: their own*
[3:55 PM] milkshakeiii: as well as some other stuff that I don't understand
[3:55 PM] milkshakeiii: they use some fairly brute-forcey approaches, not like foldit players who guide things by hand
[3:55 PM] milkshakeiii: which is why they need all that processing power
[3:55 PM] milkshakeiii: FoldIt actually gets around the need for something like Rosetta@home, ha
[3:56 PM] milkshakeiii: at least that's the way I think of it as someone who doesn't know a lot about it
[3:56 PM] Josh: HuubR About loading previous solutions to check how they score on the new metrics: would it be possible to create a sandbox for that, with all the filters + metrics available? HuubR that's a good suggestion for @bkoep , he might be able to make some kind of sandbox for binding practice, but not sure what you'd be binding to
[3:57 PM] MikeCassidytoo: A sandbox would be good
[3:58 PM] Josh: do you keep the all other solutionsnot just shared to scientist?
@pc: not sure if your question ever got answered. Yes we keep all solutions, and we collect autosaves about once every 5 minutes.
[3:58 PM] pc: A recipe that can call new metrics in lua can be very usefull too, and do the same result
[3:58 PM] pc: thanks ^^
[3:58 PM] pc: cool
[3:59 PM] HMK: Hello to everyone: btw Sandbox, will there be the option to create frozen parts of the puzzle like in 1880 (CV Binder Design) by players?
[4:00 PM] Josh: Hi HMK, I think a binder sandbox is still just a thought right now, nothing confirmed yet
[4:01 PM] HMK: would be great! :)
[4:04 PM] Formula350: While I think a sandbox puzzle would be nice. I think the main thing that would be the most help (to me, I don't know about others; our brains all learn differently lol) is the ability to not only be able to load my pre-New Metrics designs, but also still be able to use them in the Science puzzle to modify. After all, we've put in a week's worth of computational time on them. So having to try and re-create it by hand would be... well impossible heh
[4:05 PM] Formula350: (Which is why it sucks that the one "protein copier" recipe from many years ago that I found the listing for, was blacklisted, as it'd be perfect for this legitimate use. But I understand why it was removed, as it could get leveraged for cheating/stealing designs.)
[4:08 PM] jeff101:if the new metrics give drastically different scores, I think letting us reuse solutions from old puzzles won't skew the rankings a lot ... it will be a bit random how all the old solutions we saved will score with the new metrics
[4:09 PM] Formula350:I agree, because I'm also fully expecting that these old solutions would also, most times, be completely not-viable. It'd be on us whether we felt up to spending that time looking at them though
[4:10 PM] Formula350: (the ???? was a grinning emote, for those in Foldit) Opening another client window while other ones run a recipe, as I look at old designs, just makes for better use of resources.
[4:12 PM] susume: when they do Rosetta testing of foldit designs I think they do use R@h - because they have to run thousands of models to get those "funnel" graphs
[4:12 PM] jeff101:do solutions we find after a puzzle expires get stored on the server? do the scientists ever look at those too?
[4:13 PM] jeff101:I've seen many barrels lately on R@h
[4:19 PM] jeff101:Thanks to Milkshake and Josh for coming today. I enjoy these Office Hours.
[4:22 PM] pc: thanks ^^
[4:22 PM] robgee Thanks josh and milkshake
[4:23 PM] skippysk8s:k8s: yes, thanks
[4:23 PM] Dudit: thank you so much!
[4:27 PM] milkshakeiii: Thank you!

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hours 9/11/20- led by Neilpg628

12:59 PM] neilpg628: Hello All, its neilpg628 , ready to answer some questions!!
[1:00 PM] formula350: Hello Neil :D
[1:00 PM] bletchleyPark: Hi Neil
[1:00 PM] LociOilingIRC: hi
[1:01 PM] Dudit: Hello
[1:01 PM] bletchleyPark: Is there news on the paper version of the energy landscape paper ?
[1:01 PM] pc: hi
[1:01 PM] pc:There is many type of buns in the game : on loops when making tripple helix sometimes, in helix, and between player protein and target. Are they the same impact in real protein in lab? If yes, do you think we can need a different score for each?

[1:03 PM] neilpg628: To answer BootsMcGraw's question (I don't know if he is around), BUNS sometimes appear when proteins are rotated because the calculator determining if an atom is buried in the core of the protein is only an approximation, which can sometimes be tricked with a simple rotation.
[1:06 PM] neilpg628: @pc The different types of BUNS could have different levels of importance, but the ones on the interface are probably the most important, because if they are present, there might not be much of a reason for the protein to bind.
[1:07 PM] formula: Just something that came to mind... Would this be something the team might consider: adding a slower BUNS filter that had maybe twice the accuracy (but didn't contribute to points, to keep everything fair for slower system), and which operated like the current "New Metrics" that are Self-Toggled to calculate? My thought was this could at least help us refine our designs by showing which BUNS have a much higher chance of being "real" since they'd disappear compared to the Real-Time filter.
[1:08 PM] formula: (mind you, I know the New Metrics being self-toggled is not the end goal)
[1:08 PM] neilpg628: BletchleyPark, do you mean this one? https://www.biorxiv.org/content/biorxiv/early/2020/07/24/2020.07.23.218917.full.pdf
[1:09 PM] bletchleyPark: Probably, as I cannot open this link in the foldit client
[1:10 PM] formula350: I'll make a small link for oyu Bletch
[1:10 PM] bletchleyPark: The energy landcape paper, where the foldit players are co-authors
[1:10 PM] bletchleyPark: I know where to find it on biorxv, I would expect there to be a paper print version somewhere
[1:10 PM] LociOilingIRC: https://tinyurl.com/y4czb5g6
[1:10 PM] bletchleyPark: thank you
[1:10 PM] LociOilingIRC: there you are
[1:11 PM] formula350: shakes fist LOOCCIIIII!! lol
[1:11 PM] formula350: But that does have Foldit Players as authors. Titled: "Protein sequence design by explicit energy landscape optimization"
[1:11 PM] LociOilingIRC: there's also a forum post from Beta Helix today on another paper
[1:12 PM] bletchleyPark: I know the biorxv is a preprint version, is a journal version expected ?
[1:13 PM] neilpg628: It will probably me published at some time, I'm not sure when.
[1:13 PM] Dudit: Can we have an additional 'UnBun' Action button in Foldit? (similar to UnBun recipe script) ?
[1:14 PM] bletchleyPark: ok, thanks I ask because it refers to the supplemental info which I have not found online yet
[1:15 PM] neilpg628: @Formula350 The problem with a more accurate BUNS filter is that the addition that would make it more accurate is code that would be hard to integrate into Foldit (It's in Fortran, vs Foldit's C++). Including a Fortran executable in the Foldit package could be problematic
[1:15 PM] neilpg628: I have not found the Supplementary Info either, but it might not come out until the paper is fully published.
[1:16 PM] pc: I prefer a more accurate metric than a faster one sometimes ^^
[1:16 PM] formula350: OOoh ok. I thought the filter we had was capable of higher accuracy, but had been toned way down for speed. Thanks :)
[1:17 PM] pc: In the LCB1 puzzle, the solution, that work in lab in spike protein, have 30 BUNS. Maybe there is some false positives, but do you think it means some BUNS can be acceptable ? Or maybe metrics like SASA DDG and SC are good enough to find a good solution with some BUNS ? (solution have 2000 SASA). Is a large contact areas or good DDG allow more BUNS ?
[1:17 PM] bletchleyPark: @Neil I'll await the print version, thanks
[1:17 PM] neilpg628: @Dudit An 'UnBun' action might be possible, but I'll have to get back to you on that.
[1:18 PM] bletchleyPark: #fortran; can't it be rewritten in c++ ?
[1:19 PM] nspc: IMAGE: http://fold.it/portal/files/chatimg/irc_959223_1599851953.png

[1:19 PM] nspc: (a snapshoot of the LCB1)
[1:19 PM] LociOilingIRC: then there's the whole punch cards thing
[1:20 PM] nspc: (I am pc)
[1:21 PM] Jumper2: whatever the language used, just PLEASE tell me you aren't using any code from that horrible Numerical Recipes book
[1:22 PM] neilpg628: @pc Some BUNS could be false positives, but there is a point to be made that just because a particular structure (that we know folds) has BUNS doesn't imply that when designing new structures BUNS should be fine from the start. Some structures might just be exceptions, and a lot of the BUNS on the target look like edge cases that could be solved with the Fortran Code.
[1:22 PM] Dudit: Is it possible to have 0 BUNS on every puzzle?
[1:22 PM] neilpg628: There are also some licensing requirements (I think) that complicate issues.
[1:23 PM] pc: thanks
[1:23 PM] bletchleyPark: ok, thanks
[1:24 PM] neilpg628: @Dudit I can't say it's not possible, but we just want to minimize that value. Also we just revamped the BUNS filter (should be in devprev soon) that will (among other things) allow us to only penalize BUNS on particular regions of the structure. Then we can simply tell the filter to ignore the target which you cannot modify.
[1:24 PM] pc: for the LCB1 we think that some BUNS in game are bouds in lab, and this is just in the game that the fold was not perfect.
[1:25 PM] pc: (but here there is 30 buns, it is a lot)
[1:26 PM] jeff101: can you make Foldit LUA commands like isdonor(seg#,atom#) or isacceptor(seg#,atom#) to help us find donor and acceptor atoms from within recipes?
[1:26 PM] Jumper2: ooh, cool idea
[1:27 PM] neilpg628: @pc All we can say is that structures without BUNS are more likely to fold. That doesn't imply that if it folds it has no BUNS. (Affirming the consequent)
[1:27 PM] bletchleyPark: #quicksaves; can you increase the number of quicksaves to 1000 or so ?
[1:27 PM] neilpg628: @jeff101 Possibly, I am not as familiar with the Lua stuff, but probably Josh would know
[1:28 PM] jeff101: I guess isdonorH(seg#,atom#) would help too ... seems h-bonds need hydrogen atoms to be attached to the donor atoms
[1:28 PM] pc: Ok, so LCB1 is like a solution that is good enough with other metrics to have buns, but it is better without buns
[1:29 PM] formula350: Might be handy to create a Sandbox Puzzle (no Target) with Multi-Start, that has the BUNS filter and all of the Multi-Start proteins are ones that have sucessfully folded in the lab. So we can see how BUNS are on them, to get a rough idea of what MAY be "Acceptable" in our own designs.
[1:29 PM] jeff101: I like this idea Formula350
[1:30 PM] Jumper2: It may also yield clues as to where or in what particular cases buns are not a big deal or are critical
[1:30 PM] formula350: (clarification: the multi-starts would be ANY man made protein, not specifically ones players made)
[1:30 PM] Jumper2: which could then be fed back into scoring algorithms
[1:30 PM] neilpg628: @pc I suppose, but it works, so we don't touch it
[1:31 PM] formula350: That's exactly my thinking Jumper
[1:31 PM] Jumper2: As a teacher of mine use to say: "Great minds think alike, and fools never differ."
[1:31 PM] neilpg628: @pc See this paper: https://science.sciencemag.org/content/early/2020/09/08/science.abd9909
De novo design of picomolar SARS-CoV-2 miniprotein inhibitors
Targeting the interaction between the SARS-CoV-2 Spike protein and the human ACE2 receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer generated scaffolds were either built around an ACE2 helix that interacts with t...

[1:31 PM] formula350: Jeff, I'll also add your suggestion to the Requests Doc, cuz it is good as well.
[1:32 PM] jeff101: thanks. there is probably a feedback about it already
[1:32 PM] neilpg628: It was just published in Science and details the binders designed via computational methods at the IPD.
[1:33 PM] pc: in the same idea as formula, we can have some objectives available in lua, and can create a recipe to run them in any puzzles. So we can test new metrics, or more experimental or low compute metrics in any puzzles. And of course use them in recipes like "wiggle mutate" to have better heuristic.
[1:33 PM] neilpg628: That sounds like a good idea Formula350. It might be useful/
[1:34 PM] bletchleyPark: #loading and saving times; I notice that loading and saving has become slower in the clients, could this be improved ? #default tracks windows open and default recipe open ?
[1:36 PM] Dudit: I think it is a good idea to add a 'Successful Solution' in Foldit Achievement page whenever a Foldit player solution really works in the lab
[1:36 PM] neilpg628: Either @Josh or @bkoep might be more familiar with the loading and saving issues, but I personally don't know what could have caused it to change.
[1:37 PM] bletchleyPark: more complex structures and more rules perhaps ?
[1:37 PM] bletchleyPark: How about leaving the tracks windows and recipe window at their last position and poses (opened) ?
[1:38 PM] neilpg628: @Dudit That would be a very cool award to win! I think it would be easy to implement. We'll see.
[1:38 PM] Jumper2: On Dudit's suggestion, maybe even splitting it into a set of achievements for creating solutions that got physically produced for lab testing, and the higher achievement of not only being synthesized, but actually performing well in tha lab
[1:39 PM] Jumper2: So the 99 players that got something synthesized for the spike binder would get the lower achievement even though none worked, still leaving the higher level achievement to strive for
[1:40 PM] Jumper2: It's like 3d printing, it could be cool know how many times something you designed got physically produced
[1:40 PM] Dudit:
That's a great idea, Jumper
[1:40 PM] formula350: Bletchley that is how Foldit is designed, but there's a bug in the Options.txt saving right now that is preventing changes from being commited to the file. :\ (Though I suspect you may be asking for a bit more, such as loading of the track that client left off on, too?)
[1:41 PM] bletchleyPark: not necessaruly the latter, just opening the tracks window and recipe window would help already
[1:41 PM] neilpg628: Jumper, that could work as long as we have the awards infrastructure to do it.
[1:41 PM] formula350: At least, with Selection Interface... I assume that the window's location and open/closed info in the file relates to Original Interface as well... But I'm not sure <_>
[1:42 PM] Jumper2: The achievement pages generally deal with a threshhold value being crossed. I'd really love to see an actual count of got synthesized and worked in lab
[1:42 PM] bletchleyPark: I only use original interface, been here a long time ;-)
[1:42 PM] Trigger: Howdy, y'all. I joined the chat late. Is there going to be a transcript made available?
[1:42 PM] pc: yes trigger
[1:43 PM] formula350: Yep, that I know! I figured that you may use that still, afterwards hence my followup. I definitely understand hesitation to use Seleciton Interface... I was there with you. But Selection is so much more powerful that I forced myself to deal with the annoyances it has lol
[1:43 PM] nspc: https://fold.it/portal/node/2009805
[1:43 PM] nspc: you can check here trigger ^^
[1:44 PM] Trigger: Thank you, nspc:.
[1:45 PM] formula350: Neil, more a QoL quesiton that may not be applicable to you: Is it possible to have a way to highlight NEW BUNS that are present after a tool stops running?
[1:45 PM] formula350: I often have to Undo-Redo-Undo-Redo with Shown enabled in order to painstakingly find where the new BUNS(s) are. So having it turn bright-green to pinpoint them, would be great...
[1:46 PM] neilpg628: Jumper, there are achievements like 'The Write Stuff' that are managed separately from Foldit thresholds, so I think it would be possible to give players individual awards for synthesized/folded solutions.
[1:46 PM] pc: I use selection interface sometimes. It can be usefull to change only some sidechains
[1:47 PM] Xartos: oh stumbled into office hour xD hi @all
[1:47 PM] nspc: hi xartos
[1:47 PM] Jumper2: Oh, that reminded me of another wishlist item. Bands are not transparent enough. When using a band to try and create a bond between two atoms, sometimes the band hides the bond completely. I find my self doing the "R" remove bonds, then Ctrl+Z to put them back to see the bonds underneath
[1:48 PM] formula350: *waves* Hellow Xartos. Neil is the "BUNS" man, if you have any questions for him (though, if it's a general on, it probably had been asked so might need to wait till after and we can quote the answer for you)
[1:48 PM] alcor29: Is there any knowledge on how many BUNs does it take to destabilze a given quantity of hodrophobe attractions?
[1:49 PM] formula350: Jumper, are.... You a ME, transported from another multi-verse? I've made that SAME suggestion for the SAME reason!
[1:49 PM] alcor29: *hydro
[1:49 PM] formula350: (I've made so many requests prior to me keeping the doc, that half aren;'t even on it lol)
[1:50 PM] Jumper2: LOL
[1:50 PM] Jumper2: quickly hides the time machine
[1:52 PM] Skippysk8s: I'd like to see the sidechain of the bun go a different color. Half blind lol. But Neil, per PC's question -- should we worry most about buns in the center or near the binding site rather than at the edge? Are there other things you think might help us make good folds?
[1:52 PM] Xartos: main question not regarding buns or stuff... is there any attempt/aspiration to implement multi core support for foldit?
[1:52 PM] Xartos: sry old question
[1:52 PM] neilpg628: @alcor29 I don't think there is a specific ratio, but obviously fewer is better
[1:53 PM] Susume: do you have a sense of how many kJ/mol difference a BUN makes in the interface? it doesn't seem like foldit gives us that info
[1:54 PM] neilpg628: Especially for binder puzzles, BUNS near the interface are more important because in the unbound state, those polars could just bind to water. Hence there is little reason for them to be happy in the bound state when they don't have a polar partner to interact with
[1:54 PM] pc: When we use recipe like GAB, (that move protein and mutate and improve score), we have often a problem : When there is some buns between player protein and target, the recipe often detach the protein a little (and create some voids) and mutate to hydrophobic.
[1:54 PM] pc: It makes highter score, but it decrease the contact area with target ,and make a protein that have less chances to work in the lab. Do you think that add the SASA in score can resolve this problem? or there is something else usefull too?
[1:54 PM] Jumper2: Here's an idea that just popped into my head.. May be crazy, but what if you could create an alignment template from a track (you can do the opposite by creating a track and matching the template in it) It could help with BUNS if you have different tracks that satisfy different BUNS and want to create a hybrid to see if you can combine them (or just make the protein blow up most likely)
[1:55 PM]
formula350: Jumper "Load as Guide"?
[1:55 PM] Xartos: xD sounds fun
[1:56 PM] jeff101: Foldit shows the hydrogen bonds between atoms, so it must know how binds to who. Can you make LUA commands to list which seg# and atom#'s are connected by hydrogen bonds?
[1:56 PM] Jumper2: not sure about load, I was just thinking that working different tracks to attack different areas of the puzzle it would be nice to be able to combine the tracks into a possible final answer
[1:56 PM] jeff101: Also, on ligand puzzles, it would sure be nice to know how many hydrogen bonds go from the protein to the ligand. I often find myself counting them by eye, which is kind of tedious.
[1:57 PM] neilpg628: @Xartos Multicore support would be very useful, but might not be worth it, especially for Monte Carlo actions. See here: https://www.rosettacommons.org/content/abinitiorelax-using-multiple-cores-single-machine-without-mpi
[1:57 PM] bletchleyPark: @Xartos, you can run multiple clients each on their own core in a multicore machine
[1:57 PM] Jumper2: jeff: I find myself doing that too, though if available in lua, could have a quick recipe report it for you
[1:57 PM] neilpg628: tinyurl.com/y3f3enlp
[1:57 PM] formula350: @neilpg628: This sort of piggybacks off of Skippy's Q: If there's one mistake (or good thing) you keep seeing in all our results that you'd like us to be aware of so that we can stop (or continue!) doing them... What would it be? :P
[1:58 PM] Jumper2: For multi core, I was thinking of not so much speeding up computation, but for smoothing out the GUI interaction of moving the protein on the screen
[1:59 PM] neilpg628: @Xartos BletchleyPark's method is the only real way to do it. It's described in the website as well, but it's not the ideal way
[1:59 PM] Dudit: or maybe iGPU support?
[1:59 PM] Xartos: @BlechleyPark @neilpg628: doing so
[2:00 PM] bletchleyPark: I do so
[2:00 PM] bletchleyPark: have done so for many years
[2:00 PM] jeff101: The Bonding subscore gives a clue about which segments are involved in hydrogen bonds, but it doesn't say how many hydrogen bonds are made.
[2:01 PM] formula350: I think that's less an issue of Foldit being quite serialized still, but perhaps scheduler/event related? The UI waits for a certain thing to occur, and then updates. Though it could be that it's indeed handled by the same game_library thread that schedules other actions, and is indeed overworked. *shrug*
[2:02 PM] bletchleyPark: @jumper; this is already done, one thread is dedicated to GUI, the other to calculations for the main program
[2:02 PM] Jumper2: Shouldn't the bonds existing be part of the pose?
[2:02 PM] jeff101: 06pc, one way to keep the binder near the target is the recipe BandOntoSphere. Using bands with trget length 0 and strength 0.1-0.3 seems to work well.
[2:03 PM] neilpg628: @Dudit Again, that would require changes to the underlying Rosetta code. Rosetta doesn't have a lot of protocols that are open for the parallelism that a GPU offers, and I don't think anyone has tried incorporating CUDA or OpenCL into the project.
[2:03 PM] pc: thank jeff
[2:03 PM] pc: oh it is a jeff recipe
[2:03 PM] jeff101: yes
[2:04 PM] bletchleyPark: One way to speed up GUI is to disable filters while moving things around, then re-enable after positioning
[2:04 PM] formula350: It'd have to be OpenCL for the sake of universally being supported. (There's tttons of tools to port over C++ to OpenCL code available. AMD offers a ton of them for free on their Developers page)
[2:04 PM] Jumper2: I think the only possible reason for incorporating CUDA or OpenCL into Rosetta would be running on GPU farms (like certain instances that are available in the Amazon AWS cloud)
[2:05 PM] Jumper2: Granted in the supercomputing crowd, that might be appealing enough to find funding for the effort
[2:05 PM] formula350: Bletchley, while true, that's also only trying to excuse the underlying problem by coming up with work-arounds lol Really, there just shouldn't BE the level of hitching going on with the UI as there currently is.
[2:07 PM] bletchleyPark: I speak for myself, it works for me
[2:07 PM] Skippysk8s: @neilpg628, do you have advice about what is better for binding? A long connection with a bun at an edge, or a short connection that is bun free? Often we design limited interface proteins to minimize buns
[2:09 PM] bletchleyPark: I'm off to bed. I'll read up in the transcript, later, thanks Neil !
[2:09 PM] bletchleyPark: bye for now
[2:10 PM] argyrw: hi
[2:10 PM] formula350: Thanks Neil!
[2:11 PM] formula350: Oh I mistook Bletchley's message LMAO
[2:11 PM] neilpg628: @Skippysk8s I think shorter connections are better in general, because Rosetta has more difficulty predicting long loops because of the huge number of possible conformations. However, obviously too short is bad too.
[2:11 PM] formula350: IGNORE me :>
[2:14 PM] neilpg628: @Formula350 OpenCL is possible of course, and the tools do exist, but
[2:15 PM] pc: @neilpg628: When we use recipes in design puzzles, they often make a lot of hydrophobic near the target. And it is not good for the protein when it is alone in lab. Do you think we need a metric that allow hydrophobics in player protein only when : they are only inside the protein (indide a tripple helix) or near an other hydrophobic in the target ?
[2:15 PM] neilpg628: 1. Rosetta in general is not written to take advantage of mass parallelism. This is mostly because of the Monte Carlo usage, which would require most parallelism to only be don't at the highest level
[2:16 PM] argyrw: :)
[2:16 PM] neilpg628: 2. Adding OpenCL support would require the support of the entire Rosetta community (as Foldit is built on top of Rosetta) and not just us
[2:17 PM] argyrw: how you take the points of the hydrogen bond network
[2:17 PM] argyrw: ?
[2:17 PM] argyrw: I will broke it
[2:17 PM] argyrw: :)
[2:18 PM] neilpg628: Also, @milkshakeiii will be adding support for asynchronous filters soon, so the UI thread can run without blocking on filter calculations
[2:19 PM] formula350: Thankfully I'm finding stuff on Parallelizing Monte Cartlo Simulations (not by "some dude on the internet" either lol Respectable places like Oak Ridge Nat'l Labs). Using "OpenMP" was what they suggested, which was something I'd made to Josh at one time. Along with M$'s AMP
[2:20 PM] formula350: Having the UI run smoother, which it sounds like will be done with Hentry's work, will be a huge QoL improvement! :D
[2:20 PM] formula350: Henry's*
[2:21 PM] neilpg628: With regards to parallelism, I think the fundamental fact is that it would require more than just the Foldit team to agree to such a thing. There are likely other reasons for why it's not common that I'm unaware of
[2:22 PM] formula350: Yea I can recognize and appreciate how much of it is due to what can't be touched (on Foldit's end) in regards to being Rosetta code :(
[2:23 PM] Dudit: foldit multithreading?
[2:23 PM] formula350: (I'll secretly blame Moretti lol)
[2:25 PM] neilpg628: Also in some ways it might be an even harder problem on the Foldit end because we have to work on far more combinations of OS/Computer/GPU than Rosetta has to
[2:27 PM] argyrw: when you end tell me to speak to you if you want
[2:27 PM] argyrw: thank you
[2:28 PM] neilpg628: Yeah, I'll probably end now! Thanks for coming! (I'll answer one more question if anyone has one)
[2:28 PM] formula350: That's why it's important to select a universal code set, like OpenCL, OpenMP, and like is already used: OpenGL (for graphics). Then target the vendor with the fewest supported instructions (probably Intel with their older GPUs having minimal OpenCL). Integrate from there as best as possible. But that's why I think trying to parallelize the Objectives, if possible through OpenCL, would be the best 'start'.
[2:28 PM] formula350: Thanks Neild. I gained lots of insights :D

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hours 9/25/20- led by beta_helix

[9:00 AM] beta_helix: Hi everyone! Welcome to Foldit Office Hours! I'm beta_helix: (http://www.cis.umassd.edu/~fkhatib/cv.html) I've been on the Foldit Team since 2008.
[9:00 AM] Dudit: Hi @beta_helix
[9:00 AM] beta_helix: Hi Dudit!
[9:00 AM] joshmiller: hi beta!
[9:01 AM] beta_helix: I'd love to open the floor to any players that are joining our Foldit Office Hours for the first time
[9:01 AM] beta_helix: Hi Josh!
[9:02 AM] Todd6485577: morning all
[9:02 AM] beta_helix: Good morning/afternoon/evening (depending on where everyone is.
[9:03 AM] jmbrownlee333: For josh, how is the thesis proposal coming. If i dare ask.
[9:03 AM] beta_helix: I want to know that answer too!
[9:04 AM] joshmiller: oh hey jmb! sorry, I'm only half paying attention because I'm in a meeting haha (Seth is there too, we're talking about another cit sci game related to iNaturalist)
[9:05 AM] jmbrownlee333: nice multi-tasking
[9:05 AM] joshmiller: thesis proposal has been submitted, still waiting to hear back from my college on whether I'm allowed to give the proposal. Almost done with data analysis on a Foldit-related paper
[9:05 AM] joshmiller: some interesting results came out of it, lots I expected and hope to fix in future design work
[9:05 AM] beta_helix: Nice! Say hi to Seth, unless you would get in trouble for not paying attention to the meeting
[9:06 AM] joshmiller: :P nah I'll do it
[9:06 AM] beta_helix: sweet
[9:06 AM] beta_helix: I feel like Dudit is typing a novel...
[9:07 AM] Dudit: I think Foldit should have a new achievement in the Foldit Achievement page, called 'Successfull Solution' when any Foldit player solution (regardless the score) created a solution that Really Works in the Wet Lab
[9:07 AM] beta_helix: That is a great idea, Dudit!
[9:07 AM] beta_helix: and perfect timing as Josh has started looking into revamping achievements
[9:08 AM] beta_helix: (I hope I wasn't supposed to keep that a secret, Josh!)
[9:09 AM] jmbrownlee333: will we also see re-vamped categaories or updated category rankings
[9:09 AM] beta_helix: that too, jmb!
[9:09 AM] beta_helix: That should coincide with the new website we hope to launch soon
[9:10 AM] beta_helix: There are just so many things that we can't support/enhance with the current Foldit site... so it requires an entirely new website for many of these features.
[9:10 AM] beta_helix: For example: being able to view another player's solution on the site, and rotate it
[9:11 AM] Josh: haha not a secret beta_helix:, I would love to add that achievement!
[9:12 AM] beta_helix: I feel like that one is even more important than The Write Stuff
[9:12 AM] Dudit: I think there is a problem that Josh had mention it before, called 'Over Approximation', it is when the Foldit player solution scores highest but failed to work in the wet lab
[9:12 AM] beta_helix: Yes indeed, Dudit.
[9:13 AM] beta_helix: Design is very tricky, because the score function isn't as simple as with Electron Density (for example).
[9:14 AM] beta_helix: In ED puzzles, the top scores are usually spot on (or very close) to the native... unless nobody was able to reach the native fold, of course.
[9:14 AM] beta_helix: That is not the case with design, which is why the Share with Scientists feature is so critical!
[9:15 AM] jeff101: I have some questions about hydrogen bonds and disulfide bonds.
[9:15 AM] jeff101: I noticed more Shares wth Scientists on Puzzle 1890.
[9:15 AM] beta_helix: We can't test the hundreds of thousands of Foldit designs that come back, but we can easily check the Scientist Shares
[9:16 AM] jeff101: For disulfide bonds that Foldit shows and gives +250 bonuses for, I've seen negative Disulfide subscores.
[9:16 AM] beta_helix: Hi jeff101! Do you think those are more bug shares or science shares?
[9:16 AM] jeff101: I think Science Shares. Maybe the max is 10 now.
[9:17 AM] beta_helix: Hmmm... have you shared such a case so we can look into it?
[9:17 AM] jeff101:but for hydrogen bonds that Foldit shows as blue and white candy canes, I think the Bonding subscores are always positive.
[9:18 AM] beta_helix: I know that sometimes you can get the disulfide bonus even when the angle isn't great or there is even a clash.
[9:20 AM] jeff101:on 1890, I shared w/myself at some point: Je11-37 8850.298 +750 lo 9/18/20 1242am midnight
[9:20 AM] beta_helix: Ok thanks, I'll let the team know to investigate what is going on with that one.
[9:20 AM] jeff101:it has 3 s-s bonds: 2-7 w/score 6.9, 8-39 w/score -4.4, and 11-37 w/score -3.6
[9:21 AM] spvincent: Are there any tools in the works to better visualize bonding in H bond networks?
[9:21 AM] jeff101:another one, Je0 8887.278 +750 lo 9/22/20 1146pm
[9:21 AM] Dudit: I think Foldit needs more performance optimization
[9:21 AM] jeff101:had 3 s-s bonds: 2-8 w/score 2.3, 7-20 w/score -1.7, and 32-39 w/score 0.
[9:22 AM] beta_helix: @spvincent is there a specific visualization that you'd want?
[9:22 AM] jeff101:There are other cases I could find if you need them.
[9:23 AM] beta_helix: @Dudit yes, that it indeed the case. Especially if we want to be able to post larger proteins without grinding the game down to a halt.
[9:23 AM] spvincent: Better visualization of the unsatisfied bonds
[9:23 AM] beta_helix: @jeff101 Thanks! Hopefully these 2 will help us uncover what is going on.
[9:26 AM] Dudit: I wish the Office Hour is scheduled every week, I believe there are a lot of question that needs to be answered
[9:26 AM] Josh: Me too...
[9:27 AM] jeff101:For h-bonding to a particular atom, is there a limit on how many h-bonds can form? Like a on a bent O acceptor, is the most h-bonds 2 ? Do they sort of form a tetrahedron around the O atom?
[9:27 AM] beta_helix: @spvincent We are working on ways to make it easier to form proper h-bonds... particularly using rubber bands
[9:27 AM] spvincent: ok, nice
[9:27 AM] beta_helix: @Dudit Good news! You can bring this up in our new Foldit Office Hours feedback section: https://fold.it/portal/node/2010431
[9:27 AM] jeff101:Also, for a carbonyl (C=O) oxygen atom, is the most h-bonds to the O acceptor 2? Do they come in 120 degrees apart?
[9:30 AM] agcohn821: Thank you @beta_helix --glad you found that! Yes, please post feedback!
[9:31 AM] beta_helix: @jeff101 This is probably why I should have taken Organic Chemistry... too bad I was a math major in college! I don't want to give you the wrong information, so I will ask our resident biochemists on the team and get back to you on that one. (Unless any of them are online right now and want to save me.
[9:32 AM] beta_helix: @Dudit do you have any other questions that I can help answer today? (just not about O-chem.
[9:33 AM] spvincent: The puzzles have become a bit repetitive of late.
[9:33 AM] jeff101:A harder question is what is the max # of h-bonds to a nitrogen that is an acceptor atom.
[9:33 AM] jeff101:Can nitrogens even be acceptor atoms?
[9:34 AM] beta_helix: @spvincent This is important feedback that we need to hear. Thank you! What kind of puzzles are you missing? Hand-folding?
[9:34 AM] jeff101:perhaps N's on rings like C=N-C can be acceptors
[9:35 AM] Dudit: @beta_helix: Is it true that Foldit only using CPU (not iGPU) because it is using Rosetta?
[9:35 AM] jeff101:would the hydrogen bond be in a plane with the C=N-C atoms, so that all 3 angles are 120 degrees?
[9:36 AM] beta_helix: @jeff101 Thank you! I will make sure to pass all those questions to the biochem experts.
[9:36 AM] beta_helix: @Dudit Yes.
[9:37 AM] beta_helix: I was in the Baker Lab from 2008-2013 and there were a bunch of people that really wanted to push Rosetta to work on GPUs... they put in a lot of time and effort in this.
[9:38 AM] beta_helix: Ultimately, the Rosetta Community did not go in that direction.
[9:39 AM] spvincent Not hand-folding specifically. But maybe some more small molecule binder stuff: Symmetric puzzles with different numbers of monomers (what is so special about the number 3): revisiting aflatoxin: etc. Ed puzzles (even though I don't play them).
[9:39 AM] beta_helix: It might have been because there weren't enough people trying to work on it, or because they were doing this "on the side" and not as their research projects... but it essentially died out.
[9:40 AM] beta_helix: @spvincent Ok great... I was worried you were sick of design puzzles!
[9:40 AM] jeff101:reposting the ligand puzzle 1855 would be nice. the last time it was up, there was a problem with sharing solutions with teammates. if that problem is fixed, we could do much better on 1855.
[9:40 AM] spvincent: Oh no, they're my favourite.
[9:41 AM] beta_helix: I would love to bring back some ED puzzles, but it is very difficult to find density for natives that have yet to be solved or haven't been publicly released.
[9:42 AM] spvincent: And do you have an endpoint in mind for the covid design binders?
[9:42 AM] beta_helix: horowsah and I recently submitted an NSF grant to try to make Foldit ED waaaaaaaaay better... so we really hope that gets funded and we can hire a developer that will be dedicated to that project.
[9:44 AM] Dudit: @beta_helix: what is the similarity and the difference between Rosetta@Home and Foldit? Can they both be combined?
[9:44 AM] jeff101:I have more questions about hydrogen bonds. Say a certain hydrogen bond is worth 5 points in the Bonding subscore when it is from one segment to another.
[9:45 AM] beta_helix: Great question about covid. We'd have to check with bkoep and the Baker Lab, but I would guess that we will continue as long as there is no treatment available yet. Even then, these puzzles have taught us so much about how to improve Foldit for future binding puzzles (coronavirus or not). If you remember our Flu puzzles from ~10 years ago... my how far Foldit has come (both the game and all of you!)
[9:45 AM] jeff101:If similar strength bond is from one part of the ligand to another, should the Ligand's Bonding subscore also be 5?
[9:46 AM] spvincent: ok, tx
[9:46 AM] jeff101:What if the same strength hbond was between a segment on one monomer to a segment on another monomer? Would both segments have the Bonding subscore 5 ?
[9:47 AM] beta_helix: @Dudit Great question! Rosetta@home is really "donate your CPUs to Rosetta" (you let it use your computer when you are not using it) whereas Foldit is "donate your brain" as YOU are guiding the computations with your folding skills!
[9:48 AM] jmbrownlee333: chuckle
[9:48 AM] jeff101:do groups besides the Baker Lab submit jobs to Rosetta@Home?
[9:49 AM] beta_helix: Yes: https://robetta.bakerlab.org/
[9:50 AM] beta_helix: Anyone can submit a job to Robetta (the robotic Rosetta server... get it? pretty clever, right? and the jobs will be launched to Rosetta@home
[9:51 AM] beta_helix: @Dudit To address your second question.... I'd like to flip that back to all of you. How would you use R@H if we were magically able to incorporate it into Foldit?(edited)
[9:52 AM] spvincent: I've wondered where the name Robetta came from
[9:52 AM] jeff101:does Rosie send jobs to R@H ?
[9:52 AM] :jeff101:https://rosie.rosettacommons.org/
[9:53 AM] Dudit: @beta_helix: I think they should bring back Beginner Coronavirus puzzle, because it will attract more new player (including myself back then)
[9:53 AM] beta_helix: @jeff101 about your subscore 5 question... I would assume that those would act in the same way, but I will check that as well.
[9:53 AM] jeff101:I'm worried about factors of 2. Like if a bond is between 2 segments, both segments have nonzero Bonding subscores that include the 5 points from the h-bond.
[9:53 AM] beta_helix: @Dudit Thanks for the suggestion. Do you think you would still join a new project like this at this point in the pandemic?
[9:54 AM] jeff101:I'm wondering if it is different if the h-bond occurs between 2 monomers or from a ligand to itself.
[9:54 AM] beta_helix: Looking at the Rosie paper, I believe they use their own server at JHU: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063906
Serverification of Molecular Modeling Applications: The Rosetta Onl...
The Rosetta molecular modeling software package provides experimentally tested and rapidly evolving tools for the 3D structure prediction and high-resolution design of proteins, nucleic acids, and a growing number of non-natural polymers. Despite its free availability to acade...

[9:56 AM] Dudit: @beta_helix: I will do anything that I can to help regarding Coronavirus treatment!
[9:57 AM] jeff101:sometimes I hear about mutants of COVID. Maybe if you had a 3rd type of COVID puzzle, it would attract more players. Are there no other targets we could design binders for?
[9:58 AM] Dudit: There is also COVID 'Bradykinin Storm'
[9:58 AM] jeff101:also, if one of our designs shows promise, I think publicity about it will attract new players
[9:58 AM] jmbrownlee333: Protease inhibitor seem like a good target
[9:59 AM] beta_helix: Before we wrap up, I wanted to share my talk from the Bioinformatics conference that Seth and I presented at virtually over the summer. The special session was called "Bioinformatics outside the lab: How to mobilize online citizen scientists to accelerate research" https://www.iscb.org/ismb2020-program/special-sessions#sst02 and they just posted a video here: https://youtu.be/e8P1EH4WmUY?t=1
SS02-VIII: Gamers and experimentalists collaborate... - Firas Khati...

Special Sessions
ISCB - International Society for Computational Biology
[10:00 AM] beta_helix: I completely agree with your last 5 comments!
[10:00 AM] beta_helix: Thank you all for stopping by today (I now have to go feed my daughter during her lunch break)
[10:00 AM] beta_helix: Please give us your feedback about these Office Hours: https://fold.it/portal/node/2010431
[10:01 AM] jeff101:thanks for coming and thanks for having these office hours
[10:01 AM] Dudit: thanks @beta_helix:
[10:01 AM] beta_helix: Thank you all for everything that you do!
[10:01 AM] beta_helix: Keep up the great folding...

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hours 10/9/20- Led by Horowsah

[1:30 PM] horowsah: Hi all- I'm checking in for an hour of questions if you have any. No worries if you don't, but let me know. I'm not so much an expert on COVID-19 or protein design; my expertise is in electron density type stuff, education, and RNA and DNA and how they interact with proteins, especially during folding.
[1:32 PM] Enzyme2: IMAGE: http://fold.it/portal/files/chatimg/irc_104378_1602271928.png

[1:33 PM] LociOiling: IMAGE: http://fold.it/portal/files/chatimg/irc_476462_1602272012.png

[1:33 PM] LociOiling: IMAGE: http://fold.it/portal/files/chatimg/irc_476462_1602272021.png

[1:34 PM] LociOiling: IMAGE: http://fold.it/portal/files/chatimg/irc_476462_1602272056.png

[1:34 PM] Susume: hi horowsah! at one time there was talk of finding proteins published in the pdb where maybe the match to the ED was not so great, or other metrics were not so great, and having foldit players try to generate a better solution - is that still something that might happen?
[1:35 PM] horowsah: Good question, that is something we're still interested in doing and something that Foldit players can do to help, but sometimes it gets pushed to the back-burner for a bit for things we think will have more immediate scientific impact. However, we will hopefully have more of those in the not too distant future.
[1:38 PM] Susume: I think 'beating' professional scientists is very motivating to foldit players, but I'm not sure how the scientists would feel about it if they are not part of the foldit team - is there any concern about that if we target previously published proteins?
[1:39 PM] horowsah: Yes, I've thought about that quite a bit. I think most scientists are open to others helping out, so long as there's no downside for them. So it's all about how you approach the scientists with the help, even if it happens after Foldit players have worked on it. This happens between scientists as well, so it's something we're used to.
[1:40 PM] horowsah: It doesn't always work perfectly, but I don't think disasters are likely either
[1:40 PM] spvincent: I believe jeff asked a question in feedback about why the sulphur in cysteine couldn't act as as HBond acceptor: I'd be interested in hearing about that too.
[1:41 PM] horowsah: I haven't reviewed that specific case in awhile, so some of my specifics might be slightly off, but it has to do with the details of the electron lone pairs that sulfur has
[1:42 PM] horowsah: They aren't great for accepting hydrogen bonds. Technically, some would say that although they can have hydrogen-bond like interactions, they actually don't meet all of the technical criteria of a hydrogen bond
[1:42 PM] spvincent: tx
[1:42 PM] horowsah: Hydrogen bonding is something of a continuum that we've drawn lines around for what is and what isn't a hydrogen bond, and cysteine falls just outside of it
[1:43 PM] Formula350: I have 2 questions, one that I"m relaying for someone, and then my own. But I'll start with her's :P JoannaH wanted to ask if the Plasmid sequence, the Promoter, and Excretion Tag used for our proteins and both Binder puzzles, could be provided in a downloadable SnapGene format? So that she can try to express and test her protein designs at home.
[1:43 PM] jmbrownlee333: The strength od those H-bonds have been measured and they are quite weak, though not zero.
[1:44 PM] horowsah: On JoannaH's question don't know... but I know who to ask.
[1:45 PM] horowsah: @jmbrownlee333: yes, they are weak. Weak interactions can be important, but they are considered "less important" in most scenarios
[1:46 PM] Formula350: I'll let her know. As for my question (which assumes you occasionally look at player designs): What is the one biggest thing you see that we do in our designs that either: you wish we would stop doing -or- you thing is really interesting and would like more of us to do? (your choice)
[1:47 PM] Jumper2: Or both would be good too
[1:47 PM] spvincent: Is there any issue with having tryptophans on the outside of a monomer in these trimer puzzles? I know they're normally supposed to go in the interior of the protein, but with only one donor they're highly convenient for making networks fully satisfied.
[1:47 PM] Formula350: (I mean, yea, but I didn't want to hog him haha)
[1:49 PM] horowsah: It's interesting, since I'm not an expert in protein design, but more in natural proteins, I'm often surprised at the strategies that are used in protein design, because sometimes they are rather different than what's found in nature. I seem to recall looking at a really good binder the other day and being surprised at how many methionines there were at the interface. It's not something natural proteins do very often, but it seems to work well in design. So my answer really isn't all that handy from helping you to improve, but by trying things that go away from what I expect, I learn new things too. I think others on the team would say that in general, we want Foldit players, and especially experienced Foldit players to try new and different things to help us imagine what's possible that nobody's thought of yet.
[1:51 PM] horowsah: Tryptophans... I'm not familiar with all the details on the trimer puzzles, but tryptophans can be a bit deceiving. There are occasionally natural proteins with exposed tryptophans, but they're pretty rare. From an evolutionary perspective, tryptophan actually is the hardest amino acid to change, which is a bit surprising that it outranks things like glycine and proline. So while it seems like it should be used in a lot of circumstances, nature thinks it's only good for very specific spots, and then never tries to change it.
[1:52 PM] horowsah: Not sure if that actually answers the question, but that's the thing that comes to mind.
[1:53 PM] spvincent: interesting: tx
[1:53 PM] Formula350: I wouldn't be surprised if that design was mine. I'd been trying a couple MET-based solutions. Thanks for that, though (even if it wasn't mine) as I that's exactly the encouragement I wanted to hear; think outside the box.
[1:53 PM] Susume: cool! does nature use tryp in binding interfaces much, or only inside the monomer?
[1:54 PM] horowsah: In my experience, tryptophan is usually internal, except when binding a nucleic acid or nucleotide, where it can stack great with purines. There's probably other examples as well, but those are the only ones coming to mind.
[1:55 PM] Formula350: As an add-on to Susume's, do they often use the Tryp to make HBonds, or are they utilized for their Pi Bonding?
[1:56 PM] horowsah: The h-bond is handy as a way to give specificity, but from what I've seen the stacking is used more when binding other things. When it's a monomer, it's harder to tell, as it's nearly impossible to change one without changing the other in most cases. That might be part of why it's so hard to change via natural evolution.
[1:58 PM] horowsah: I have a question for all of you, actually. When you use the auto-mutate function in a design puzzle, how often do you go in afterwards and change stuff vs accepting what it gives you?
[1:58 PM] jmbrownlee333: for myself, id say almost never.
[1:59 PM] Enzyme2: immediately change them manually. For me rarely. Usually I freeze it if I don't want it to change
[1:59 PM] Formula350: As a hand folder, myself, I do it quite often. A lot of times it's because the Auto-Mutate doesn't "see" the possibilities, and doesn't place in (even at low low CI) what could work well. Where at low CI it likes to inject Phobics instead.
[1:59 PM] spvincent: rarely. Prolines have to be changed manually and sometimes its nice to use asparagine to fix up a Bun
[2:00 PM] jmbrownlee333: I do like to run mutate_no_wiggle occasionally
[2:00 PM] Susume: I watch for places where it put a hydrophilic in the core and change those by hand, and try to figure out how to stop it making the same change again in that spot
[2:01 PM] Formula350: That's why I'm hoping for a feature I'd requested to be approved: White/Blacklisting of AAs in the menu (like how we're blocked from even using them), to make it so the Auto-Mutate tool won't use them. To save myself time from manually brute-force checking all the kinds I'm wanting to try. lol
[2:01 PM] Jumper2: Depends on circumstances, I try to use it to stabilize a protein that I'm trying to get into shape near the beginning. So if you get it into a close position, but afraid it might fly apart if you wiggle, I find the auto mutate at that point to be nice. Then I might hand mutate some to further guide where I want it to go
[2:02 PM] HuubR: I normally watch what Mutate gives me, and when I do not like it (Buns!) I stop it and go one or two steps back, freeze that sidechain, and restart Mutate
[2:02 PM] MikeCassidy: When I have bad loops I manually change them sometines
[2:02 PM] horowsah: @Formula350, that's a feature we've been talking about; not sure if/when it will make it in, though.
[2:02 PM] Formula350: I do as HuubR as well.
[2:02 PM] Formula350: I'll keep my fingers crossed, then
[2:03 PM] jmbrownlee333: I have a random question. why do we start with poly ile
[2:03 PM] horowsah: Ha! I don't know, but let me ask.
[2:04 PM] Susume: sometimes I will manually change all surface proteins to glu or some other blue and see what mutate tool does from there, as a way to jump to a new set of AAs for the same bakcbone
[2:05 PM] MikeCassidy: i also do a 'semi' hand change: I run amutate script on one seg I dont like and see the highest score that isnt what is there then manually change that
[2:05 PM] horowsah: thanks on the thoughts about hand vs auto mutate. I've been thinking about it frequently lately, and wasn't sure how people actually used it.
[2:05 PM] HuubR: My guess would be: Isoleucine is an average size, and no polar atoms on the sidechain to stick to places where you don't want it to, during initial folding. It works fine for me :-)
[2:06 PM] horowsah: Probably average size is a good reason; but I could imagine other choices as well that would work.
[2:06 PM] Susume: they used to give us all alanine, but then our backbones ended up too close together
[2:06 PM] jmbrownlee333: I think its kinda bulky, I think poly val might be an inyteresting twist.
[2:06 PM] horowsah: Yeah, that makes sense, and would mostly be a size thing
[2:07 PM] HuubR: I used VAL earlier on, but I came back from that because the backbone gets too tight for mutate (later on) to have enough choices.
[2:09 PM] jmbrownlee333: I have an education question. Has folditEducation been well received? and is there any community of teachers built around it that you know of? Just FYI I have not used it in the classroom.
[2:10 PM] horowsah: We don't require educators to tell us when they use it, so we don't know completely, but I know of at least ~30 educators using it right now. I'm assuming there are many more who are using it but haven't told us. So far, we haven't had any major complaints, but I expect we'll get more feedback in the next month or so.
[2:12 PM] jmbrownlee333: At what education level do you think its most effective?
[2:12 PM] malphis: I use auto-mutate quite a bit to stabilize before wiggling. Otherwise I'll use a script like Local Mutate. I rarely change individual sidechains by hand.
[2:13 PM] horowsah: We designed Edu Mode to be most complementary to an undergrad biochem class, but I think it would work well in part of a lower level college bio class as well. In the long term, we'd love to make multiple versions aimed at different education levels.
[2:14 PM] HuubR: In your introduction, you spoke about RNA and DNA and how they interact with proteins, especially during folding. I've been wondering whether it makes a difference for folding (in nature!) when you have a helix followed by sheets, or the other way around. Is the first part of the peptide chain already folding while the tail end is still "being assembled"?
[2:15 PM] horowsah: Yes, typically as proteins are synthesized, they start folding before the whole chain is done. So the order is important for having it fold properly in a natural environment. It helps that the ribosome is in itself a pretty good chaperone, and that there are chaperones standing at the ready to help as well, but there are also cases in the literature where you can change the ordering, and it no longer folds properly because it folded in the wrong order while being made.
[2:17 PM] HuubR: So if I design something in Foldit that has a helix at the end, and sheets around that helix preceding it in the sequence, that is not likely to fold like that?
[2:17 PM] Dudit: @horowsah Do we need to understand the protein science to be a good Foldit player?
[2:18 PM] Jumper2: I had thought that might be the case, so on some puzzles, I've tried freezing everything, then slowly unfreezing starting at the first residue. But foldit and I guess rosetta don't seem too well designed to work from an original denatured peptide chain to get to a good fold. It seems you need to get it close to right and foldit will help tweak it an improve it
[2:18 PM] horowsah: @HuubR, it's hard to predict beforehand. Our usual strategy is if it's a stable protein, it will often work fine even if the order of the secondary structures isn't optimal. It's something I'd love for us to improve on predicting.
[2:19 PM] horowsah: @Dudit, that's something I actually don't know the answer to, but I'd be really interested to hear what other vets think.
[2:21 PM] jmbrownlee333: The most successful folders historically dont start out from protein scientist background.
[2:21 PM] Formula350: I continually express that I know nothing about BioChem, and what little I do know, Foldit and the community has taught me. Whether or not I'm a "good folder" (as in, scientifically, if my results are good), I can't say. I'd like to think I am, especially given my limited knowledge
[2:21 PM] Susume: there is that dataset of 4000 foldit designs, I wonder if one could analyze them for short-range vs long-range interactions, how close are the short-range ones to the N-terminal, and does that correlate to in silico success (folding funnel goodness) or invitro success (only have the smaller 145-design dataset for that)
[2:21 PM] HuubR: Depends on what makes a good Foldit player. Playing for points, no, you just need to understand the scoreboard. Playing to help science, yes, some knowledge might help. But on the other hand, too much bias is not good either (as Formula350 is also pointing out :-)
[2:23 PM] jmbrownlee333: I spent more than ten years as a Protein Scientist and I am a middling folder. Thats not data, just anecdote sample size=1.
[2:23 PM] horowsah: I'm going to bring the question of the ordering up. If you're curious, the technical term used typically is called "co-translational folding". Translation is the process of the protein being synthesized, so the term refers to the folding starting before it's done with synthesis. I don't know how well we handle it now, but I'm assuming there are ways we can investigate it, as Susume mentions.
[2:25 PM] jmbrownlee333: It probably helps that we are designing small proteins. which might have smaller problems folding
[2:25 PM] horowsah: I should also mention that I am a biochemist, and I'm not very good at Foldit. I often get paralyzed by trying to fit things into how I've been taught it "shoud" work.
[2:26 PM] jeff101: for tryptophan pi-stacking, which part matters more, the 5-membered ring or the 6-membered ring?
[2:27 PM] Formula350: @Dudit I think having a good understanding of certain things that Foldit doesn;'t directly teach you, is very good (ie Pi Stacking). Knowing very little though, helps, as it lets you think outside the box easier. There's also a lot of ""stupid stuff"" I've done when designing a protein, that later on (say, last week lol) I come to find out, it's a legitimate motif! https://en.wikipedia.org/wiki/Protein_tandem_repeats
Protein tandem repeats
An array of protein tandem repeats is defined as several (at least two) adjacent copies having the same or similar sequence motifs. These periodic sequences are generated by internal duplications in both coding and non-coding genomic sequences. Repetitive units of protein tand...
[2:27 PM] horowsah: Not speaking from an energy perspective but from what I'm seen more typically, the 6-membered ring. But I could be wrong on that one.
[2:27 PM] jeff101: does it use the 6-membered ring to stack with phe and tyr? does it use the 5-membered right to pi-stack with his?
[2:27 PM] Formula350: (in game chatters: that's Protein_tandem_repeats)
[2:27 PM] horowsah: If you're curious, tandem repeats tend to be really good for interacting with other proteins
[2:28 PM] jeff101: do the rings all tend to line up parallel to each other like a stack of pancakes?
[2:28 PM] jeff101: are their centers generally lined up, or is it better to slightly shift their centers from each other?
[2:28 PM] horowsah: pi stacking can have other arrangements, but usually the most favorable would be pancake-style
[2:28 PM] horowsah: Typically, centers are close, but depending on the exact stackers, they can be offset some
[2:29 PM] horowsah: I have to go in a couple minutes, but any last minute questions?
[2:30 PM] HuubR: In the Electron Density puzzle last June (1847), I noticed that at the perimeter of the cloud, there are some parts missing, and other parts seem to be left over from adjacent molecules. Is that due to the fact that the Electron Density map is measured on a crystalline form of the protein, i.e. with a repeating pattern? And if so, how do you know where to cut this pattern to obtain the map for just that one monomer?
[2:30 PM] jeff101: do you have your class playing a contest on Foldit? what should we do when students ask questions on Global Chat?
[2:31 PM] horowsah: @HuubR Yep, that's the basic reason, and it can be really hard at the beginning. Often, it's trial and error for awhile. There are some computational tools that can help, but often they screw it up too.
[2:31 PM] jeff101: are there ways Foldit can block Global Chat so students in certain classes cannot use Global Chat?
[2:32 PM] horowsah: @jeff101: Yes, I and others do have students playing contests. There are ways we can block it if the educator wants to, but we've typically left it up to them. This has been something we've debated about how to deal with best.
[2:32 PM] jeff101: as a teacher, you might want to block your students from using Global Chat so they can't get help from other Foldit players
[2:32 PM] MikeCassidy: Yes I am always wondering if I am helping students too much BUT I dont always know if it is a student or someone like myself just playing
[2:32 PM] Skippysk8sIRC: or use us as a cheap teaching assistant lol
[2:33 PM] HuubR: jeff101, this reminds me of a post on the forum:
[2:33 PM] HuubR: https://fold.it/portal/node/2009529
[2:33 PM] Formula350: Yes, I tried a Tandem Repeat this last time on the Spike puzzle! It... didn't play out so well, but I didn't get to devote as much time to it. I named it the "Triple Deuce" (a musclecar term).
[2:33 PM] horowsah: Personally, I don't mind if they get help from other Foldit players, because they still have to actually do it themselves. My primary concern is overtaxing our players with a lot of questions that their instructor should be answering instead.
[2:33 PM] Skippysk8sIRC: we can always need to answer the phone ;)
[2:34 PM] jeff101: it would help to have videos of solving the Edu puzzles if they differ from the usual Intro Puzzles
[2:34 PM] horowsah: It probably would be... something to think about.
[2:35 PM] horowsah: I have to head to another meeting, thanks everyone!
[2:35 PM] Formula350: I've personally abstained from providing too much help to students so that they can still "discover" the answer/solution. Personally I've found that being given the answer hasn't exactly helped my learning heh Though, certaintly there are times it has, so it's tough to say <_>
[2:35 PM] Skippysk8sIRC: thanks
[2:35 PM] Formula350: Thanks Horowsah!
[2:35 PM] Dudit: thank you @horowsah
[2:35 PM] jeff101: yes. thanks for coming. I enjoy these office hours.
[2:36 PM] HuubR: Thank you, horowsah!
[2:36 PM] Susume: thanks horowsah!
[2:36 PM] MikeCassidy: Thanks for the talk

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hours 10/17/20- led by Bkoep

10:59 AM] bkoep: Okay, office hours are open!
[10:59 AM] donuts554: hello
[10:59 AM] bkoep: I'm a scientist at the UW Institute for Protein design, and I oversee a lot of Foldit's protein design puzzles. Happy to take any questions about Foldit and/or protein design!
[10:59 AM] formula350: Hello Sir
[10:59 AM] BletchleyPark: Hello bkoep
[11:00 AM] donuts554: hello how are you?
[11:00 AM] Dudit: Hi Bkoep
[11:00 AM] alcor29: Any news on LCB1 trials?
[11:01 AM] BletchleyPark: Is there news on the energy landscape publication ?
[11:01 AM] Dudit: Is it possible to design any protein that didn't require any energy at all?
[11:01 AM] bkoep: Any news on LCB1 trials? @alcor29 No, the last I heard was preparations for experiments in mice, and maybe non-human primates
[11:01 AM] alcor29: Tx bkoep.
[11:03 AM] bkoep: BletchleyPark: Is there news on the energy landscape publication ?
It has not yet been accepted by a journal for publication. We recently heard back from the editor who wanted some revisions (normal for any paper)
[11:04 AM] BletchleyPark: ok, thank you. Is it possible to ass the supplmental list of foldit players to the preliminary publication ?
[11:04 AM] BletchleyPark: to add
[11:04 AM] pc: :D
[11:04 AM] bkoep: Is it possible to design any protein that didn't require any energy at all? @Dudit Can you elaborate what you mean?
[11:05 AM] pc: is it possible to create variant of LCB1 protein that work in lab, or when we change one AA, its moslty doesnt work anymore ?
[11:06 AM] MikeCassidytoo: hi all
[11:06 AM] donuts554: hello how are you?
[11:07 AM] Dudit: A working and folding protein that is using no energy, because the current design is still using energy (maybe thermodynamic factor)
[11:07 AM] bkoep: BletchleyPark: ok, thank you. Is it possible to ass the supplmental list of foldit players to the preliminary publication ?
I'm not sure if we will be able to revise the authors. But if you played the old monomer design puzzles and would like to be added, it wouldn't hurt to fill out the authorship form
[11:07 AM] bkoep:
Google Docs
Energy Landscape Optimization Paper
This form is open to all Foldit players who have played a "Monomer Design" puzzle in Foldit (like Puzzle 1698: Medium Monomer Design). Researchers at the Baker Lab have used Foldit players' work to help develop a new method for designing proteins. They are preparing a researc...

[11:08 AM] BletchleyPark: I played the puzzles and I received the authors list, but that list is not part of the current online publication, hence we're not credited as individuals, other than 'foldit players '
[11:10 AM] bkoep: is it possible to create variant of LCB1 protein that work in lab, or when we change one AA, its moslty doesnt work anymore ?
@pc: I'm not sure what you're getting at. But the original LCB1 paper described the effects of mutations to LCB1 (fig 2)
[11:10 AM] bkoep:
De novo design of picomolar SARS-CoV-2 miniprotein inhibitors
Targeting the interaction between the SARS-CoV-2 Spike protein and the human ACE2 receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer generated scaffolds were either built around an ACE2 helix that interacts with t...

[11:10 AM] pc: thanks
[11:10 AM] bkoep: (I apologize if that article is behind a paywall)
[11:11 AM] susume:
Baker Lab
Publications - Baker Lab
To read an article, click on its title and select the PDF file. Use the box below to search publications.
[11:12 AM] susume: you can click on article title here and get free pdf
[11:12 AM] bkoep: A working and folding protein that is using no energy, because the current design is still using energy (maybe thermodynamic factor)
@Dudit Protein folding is passive for all of our protein designs. The folded state has a lower free energy than the unfolded state
[11:13 AM] bkoep: We have a deeper discussion about free energy and protein folding on the blog
[11:13 AM] bkoep:
The problem of protein design
The problem of protein design
[11:14 AM] formula350: Clickable:
[11:14 AM] formula350: https://fold.it/portal/node/2005623
The problem of protein design
The problem of protein design
[11:14 AM] donuts554: I thought that a string of glutamatic acid residue didnt need any energy to fold
[11:14 AM] alcor29: On the two sided interface puzzle. Do the two helixes have to exactly that far apart? Could they have been a bit closer to each other?
[11:15 AM] bkoep: BletchleyPark: I played the puzzles and I received the authors list, but that list is not part of the current online publication, hence we're not credited as individuals, other than 'foldit players '
That's right, the pre-print was posted early, before players had much chance to fill out the authorship form. The pre-print does not include individual Foldit player names, but any final publication will include all names -- probably in the supplementary info.
[11:15 AM] jeff101: have you ordered any Foldit-designed binders lately?
[11:15 AM] Dudit: How many % probability of successful working protein design from Foldit player in the wet lab if the new metrics (DDG,SASA,SC) is applied?
[11:16 AM] susume: is there a comment area on the preprint where you could link to a page listing individual authors?
[11:16 AM] bkoep: On the two sided interface puzzle. Do the two helixes have to exactly that far apart? Could they have been a bit closer to each other?
@alcor29 Yes, we're interested in an interface that is compatible with that exact distance between the two hairpins
[11:17 AM] bkoep: This is a general problem in protein design, and one that our computer algorithms are particularly poor at. So this two-sided interface puzzle is an exciting pilot experiment for us.
[11:17 AM] bkoep: Depending on the results, we may see a lot more like it
[11:18 AM] alcor29: On DDG. Am able to get the metrics spot on but it means going contrary to my intuition. Does that interfere with the human contribution to protein folding design.
[11:19 AM] bkoep: jeff101: have you ordered any Foldit-designed binders lately?
No, we haven't ordered any more designed binders for lab testing. We know that we need to work on the properties of our designs in Foldit. We won't want to run another lab experiment until we have the new Metrics in place and have more designs that satisfy our Metric thresholds
[11:21 AM] donuts554: Yes the Metrics are important
[11:21 AM] bkoep: How many % probability of successful working protein design from Foldit player in the wet lab if the new metrics (DDG,SASA,SC) is applied?
@Dudit It's hard to say for certain. But LCB1 was selected with very similar metrics, as part of a pool of 100,000 designs. They found about 100 hits in that experiment, so that's a success rate of 0.1%.
[11:21 AM] Dudit: I think there should be a new list in the Achievement page called 'Successful Working Solution' when any Foldit player protein design works successfully in the wet lab
[11:22 AM] BletchleyPark: What is the real-world purpose of the two-sided interface problem ? and there is still an open question from Susume
[11:23 AM] jeff101: if a segment is involved in pi-stacking, what subscores will best reflect this?
[11:24 AM] jeff101: do only trp, phe, tyr, and his do pi-stacking? can arg and pro do it too?
[11:24 AM] bkoep: On DDG. Am able to get the metrics spot on but it means going contrary to my intuition. Does that interfere with the human contribution to protein folding design.
@alcor29 Not at all! There will always be some amount of learning for humans to play Foldit and contribute to protein design. There are also matters of presentation and communication -- we may be able to improve how DDG is presented in Foldit, in a way that makes it more intuitive to address.
[11:25 AM] donuts554: I dont think arg and pro can do it because they are not aromatic
[11:25 AM] HuubR: About "designs that satisfy our Metric thresholds": do you mean that, for instance, the DDG has to be -40 or better, or otherwise the solution will not be viable in the wet lab?
[11:25 AM] alcor29: k
[11:27 AM] Skippysk8sIRC: donuts, pro isn't an aromatic but it has a loop. arg is totally different
[11:27 AM] formula350: Donuts: Arg can Stack, and funny Jeff mention Proline, as I came across an instance in the Aflatoxin the day before where it certain looked like the PHE and PRO were stacking (based on Sphere view)
[11:27 AM] formula350: certainly*
[11:28 AM] bkoep: is there a comment area on the preprint where you could link to a page listing individual authors?
@Susume Maybe... although I'm not sure if that would meet the comment policy of biorXiv
[11:28 AM] alcor29: Is there any way of introducting more flexibility in structures. For exmample, to satisfy the new metrics it might help if the sss could bend a little?
[11:29 AM] bkoep: I think there should be a new list in the Achievement page called 'Successful Working Solution' when any Foldit player protein design works successfully in the wet lab
@Dudit I like this idea, but we are not set up very well to support it right now
[11:29 AM] alcor29: Might be a par tof the wiggle function. Or the rigidity may just be an artifact of the graphic representation.
[11:32 AM] Skippysk8sIRC: to Alcor's question, does tighter binding of side chains or SS make the shape conform better?
[11:32 AM] bkoep: BletchleyPark: What is the real-world purpose of the two-sided interface problem ? and there is still an open question from Susume
This particular puzzle would help with an IPD project about modular protein complexes. If we decide to run more puzzles like it, then I think the project leader would write up a full blog post with details about the project
[11:32 AM] BletchleyPark: ok, thank you
[11:33 AM] pc: this should be on puzzle description ^^
[11:33 AM] BletchleyPark: Which supercomputer did you use to generate the big set of proteins for covid ?
[11:33 AM] donuts554: I have 3 questions
[11:34 AM] alcor29: Thanks Skippy. Good addition.
[11:34 AM] bkoep:, jeff101: if a segment is involved in pi-stacking, what subscores will best reflect this?
Rosetta/Foldit actually does not have a term for pi-stacking. So the energy associated with complementary pi-orbitals is not included in Rosetta calculations. This may change in the future, but for now, stacked aromatics should still have a good Packing subscore.
[11:35 AM] donuts554: One is what is the purpose of the dense concentration of oxygen atoms in front of the locked receptor part in puzzle 1855?
[11:35 AM] donuts554: https://fold.it/portal/files/chatimg/irc_902783_1593572159.png
[11:36 AM] formula350: (I've observed very good Packing in my Pi Stacked instance, for whatever that's worth for ya, Jeff)
[11:36 AM] donuts554: Two is are these sheets and why or why not?
[11:36 AM] donuts554: IMAGE: http://fold.t/portal/files/chatimg/irc_902783_1602956212.png
[11:37 AM] Dudit: I think there should be a Bradykinin Storm Coronavirus puzzle in Foldit
[11:37 AM] formula350: (Highest, albeit in the middle of a Trimer, was over 200 on that Subscore, between PHE)
[11:37 AM] bkoep:
@HuubR: About "designs that satisfy our Metric thresholds": do you mean that, for instance, the DDG has to be -40 or better, or otherwise the solution will not be viable in the wet lab?
I mean that we have evidence that these Metric thresholds improve success rates. Even when we meet these thresholds, our success rate is somewhere around 0.1%. If we don't meet the Metric thresholds, we expect our success rate will be less than that.
[11:38 AM] HuubR: Thanks
[11:40 AM] pc: oh that means we realy need a very good ddg
[11:40 AM] donuts554: And three is that is a design like this stable, and why or why not?
[11:40 AM] donuts554: https://fold.it/portal/files/chatimg/irc_902783_1596412421.png
[11:40 AM] donuts554: https://fold.it/portal/files/chatimg/irc_902783_1596414166.png
[11:41 AM] pc: 1500 sasa and -40 ddg are hard to reach in design puzzles. We are often in 1300 sasa and -35 ddg in mostly top solutions
[11:41 AM] Skippysk8sIRC: so back to alcor's question perhaps?
[11:43 AM] bkoep: Is there any way of introducting more flexibility in structures. For exmample, to satisfy the new metrics it might help if the sss could bend a little?
@alcor29 This is a little bit dangerous, and we should be careful about over-optimizing with the metrics. The metrics are useful for evaluating whether a protein interface looks good. But we need to be very cautious about how much alter our models to make them conform to the Metrics. You might be able to get better SASA if you bend your helices, but bent helices can also make your protein design unrealistic and unlikely to fold
[11:44 AM] bkoep: There is perhaps an element of Goodhart's Law in that concern with the metrics
[11:44 AM] HuubR: "When a measure becomes a target, it ceases to be a good measure."
[11:45 AM] HuubR: (had to look that up :-)
[11:45 AM] bkoep: BletchleyPark: Which supercomputer did you use to generate the big set of proteins for covid ?
The UW has a large computer cluster that we can use, and we also have a pretty nice cluster at the IPD itself
[11:46 AM] pc: If the measure need to resolve lot of difficult constraints to have hight score, it can be a good measure(edited)
[11:47 AM] BletchleyPark: ok, thanks, I thought you had used ORNL
[11:48 AM] bkoep: donuts554: One is what is the purpose of the dense concentration of oxygen atoms in front of the locked receptor part in puzzle 1855?
I'm not sure! I don't know a lot about the Y1 receptor in Puzzle 1855, but those oxygens could be important for how the Y1 protein associates with other proteins
[11:48 AM] BletchleyPark: (my suggestion to Baker Lab last year)
[11:48 AM] Skippysk8sIRC: how much might a real protein shape change when it binds to something? We know that the Covid spikes have hinges and move. Is this atypical?
[11:49 AM] formula350: @bkoep Something I've been trying to ask at Office Hours lately: What is one of the most common things you see us doing with our designs that either: you wish we would cut back on -or- you think is really interesting and would like it if more of us did it? (your choice; answering both is always welcomed lol)
11:49 AM] bkoep: donuts554: Two is are these sheets and why or why not? donuts554: IMAGE: http://fold.it/portal/files/chatimg/irc_902783_1602956212.png
I'm worried there is not enough hydrogen bonding between those sheets. Beta sheets should form a ladder of H-bonds between adjacent strands
[11:49 AM] formula350: (Skippy seems to be asking about Conformal Change (something JoannaH is hoping might be a thing Foldit can incorporate/explore)
[11:50 AM] bkoep: donuts554: And three is that is a design like this stable, and why or why not? donuts554: https://fold.it/portal/files/chatimg/irc_902783_1596412421.png
It's hard to tell from the images, but I'm concerned that this protein lacks a well-packed hydrophobic core.
[11:54 AM] BletchleyPark: Can foldit be compiled for 64-bit use as well to overcome size limitations ?
[11:55 AM] jeff101: @bkoep, thanks for having this Office Hour and for all your answers so far
[11:55 AM] bkoep: Skippysk8sIRC: how much might a real protein shape change when it binds to something? We know that the Covid spikes have hinges and move. Is this atypical?
This is a tricky subject. In natural systems, it is common for proteins to change shape upon binding (you can probably find more resources online about "induced fit"). However, there is usually some energy cost associated with that change in shape (otherwise, the protein would have take that shape from the start). If you can design a folded protein that is pre-organized in exactly the shape in needs to bind, then you can avoid that energy cost and improve the binding affinity.(edited)
[11:55 AM] Jumper2: I would expect that handling conformal changes would be rather difficult to add into the code given that it turns a puzzle session into multiple parallel sessions each trying to get to a different solution. If I had to try it today with Foldit, I'd probably try to set up each conformation as a track, possibly bring in the alignment tool. On a similar note, has anyone noticed if the set of Foldit players solutions for a particular puzzle end up finding multiple conformations?
[11:56 AM] jeff101: the Partition Puzzles from 2019? dealt with that
[11:57 AM] Jumper2: It would be somewhat heartening to know that when looking at the set of all solutions for a puzzle, that we at least manage as a group to statistically cluster around known conformations
[11:58 AM] donuts554: But it does form a ladder of Hydrogen bonds both on the x and z axes
[11:58 AM] donuts554: IMAGE: http://fold.it/portal/files/chatimg/irc_902783_1602957529.png
[11:59 AM] donuts554: IMAGE: http://fold.it/portal/files/chatimg/irc_902783_1602957544.png
[11:59 AM] donuts554: IMAGE: http://fold.it/portal/files/chatimg/irc_902783_1602957552.png
[11:59 AM] BletchleyPark: #binders If we find a binder for Covid, what are the odds it will make it into real medication ?
[12:00 PM] susume: that's very pretty, donuts
[12:00 PM] jeff101: The Partition Function Tournament of 2018:
[12:00 PM] jeff101: https://fold.it/portal/node/2005623
The problem of protein design
The problem of protein design
[12:01 PM] jeff101: https://fold.it/portal/node/2005638
Partition functions
Partition functions
[12:01 PM] jeff101: https://fold.it/portal/node/2005660
Protein Design Partition Tournament
Protein Design Partition Tournament
[12:01 PM] jeff101: https://fold.it/portal/node/2006103
Partition Tournament Final Results
Partition Tournament Final Results
[12:02 PM] formula350: @bkoep Something I've been trying to ask at Office Hours lately: What is one of the most common things you see us doing with our designs that either: you wish we would cut back on -or- you think is really interesting and would like it if more of us did it? (your choice; answering both is always welcomed lol)
In the symmetric trimers, we have to reject a lot of designs because they rely on a tight triangle of H-bonds in the middle of the protein (with TYR, THR, or SER residues). These "networks" score better than they should in Foldit, and we've been trying to figure out a good way to fix it. Ideally, the angle between H-bonds is usually tetrahedral (109 degrees) or trigonal planar (120 degrees); these tight triangles require three close-proximity H-bonds at 60 degree angles.
[12:02 PM] alcor29: On the two sided interface. There seems to be a difficulty in getting rid of non-ideal loops due to the distance. Is that just something we need to overcome, or are non-ideal loops kind of to be expected?
[12:02 PM] bkoep: I talked about these triangles a little bit in one of the recent Lab Report videos
[12:03 PM] formula350: That's good to know, thank you :)
[12:04 PM] bkoep: BletchleyPark: Can foldit be compiled for 64-bit use as well to overcome size limitations ?
I'm not certain what size limitations you mean? Our mac version of Foldit is compiled for 64-bit and we haven't noticed any significant differences in performance
[12:04 PM] pc:: yes this kind of informations are very usefull for us ^^ (nice question formula )
[12:04 PM] robgee: Bah... those tight triangles are the easiest to make :p
[12:05 PM] pc: why some design puzzles allow threonine serine, and other design puzzles not?
[12:05 PM] LociOilingIRC: skip the triangles...more cowbell
[12:05 PM] jeff101: :)
[12:06 PM] BletchleyPark: #64bit I recall 32-bit windows clients crashing when they memory usage reaches around 1.6 Gb
[12:08 PM] BletchleyPark: The protein design sandbox puzzle will crash eventually
[12:10 PM] bkoep: BletchleyPark: #binders If we find a binder for Covid, what are the odds it will make it into real medication ?
It's a long road from the lab to the pharmacy. Especially because de novo protein design is so new and, to my knowledge, no de novo protein has been approved by the FDA (I think the closest might be Neoleukin's IL-2/15 mimetics, which may start clinical trials soon). So, hopefully we will have something effective for COVID-19 long before our binders have a chance to make it to the shelves
[12:12 PM] BletchleyPark: thank you
[12:12 PM] bkoep: (We are hopeful the path-to-pharmacy may get shorter in the future as more de novo protein drugs are developed. So the next pandemic could be a different story)
[12:13 PM] Skippysk8sIRC: is it getting easier to get AAs for the wet lab now? or is the supply chain still running slow
[12:14 PM] bkoep: On the two sided interface. There seems to be a difficulty in getting rid of non-ideal loops due to the distance. Is that just something we need to overcome, or are non-ideal loops kind of to be expected?
@alcor29 Yes, that's a known bug. The Ideal Loops Objective was not designed to work with chain breaks. I believe it will be impossible to completely satisfy that Objective in the puzzle, but hopefully we can do something to ameliorate the issue in future puzzles
[12:15 PM] HuubR: (Was that a challenge to all of us?)
[12:15 PM] mikelewis: haha I thought the same thing Huubr
[12:16 PM] formula350: @Jumper2 I wonder if it would genuinely be that "hard" to accommodate a Conformation System... I think the Devs technically have all the 'tools' right now that would allow it. As in, allowing certain backbone segments unlocked status, but having Constraint Bans of a weak strength attached (and probably attached to their Bondable atoms) to literally "keep them on a short leash".
[12:17 PM] formula350: That would allow them to move a bit, to conform, but not have totally free movement like we do in our own proteins.
[12:17 PM] bkoep: why some design puzzles allow threonine serine, and other design puzzles not? @pc: Good question! There is some evidence that SER and THR can interfere with how helices fold, so we like to avoid those residues in helices if possible. However, SER and THR are really useful for H-bond Networks and satisfying BUNS, so sometimes we allow them.
[12:18 PM] pc:: thanks
[12:20 PM] alcor29: Thanks for the ov hour plus plus bkoep!
[12:20 PM] mikelewis: Yep, thanks!
[12:20 PM] Skippysk8sIRC: yes, thanks. We look forward to the working binder metrics
[12:20 PM] pc: yes thanks ^^
[12:21 PM] formula350: *bows* Thank you, Science Senpai, for recognizing us.
[12:21 PM] Dudit: @bkoep thank you very much!
[12:21 PM] pc: dont hesitate to experiment multiple new metrics score system in devprev, we will test them
[12:21 PM] jeff101: Saturday seems like a good time for Office Hours. Seems like many people came today.
[12:22 PM] Skippysk8sIRC: I gave up my second farmer's market for this... maybe lost out on melons
[12:22 PM] BletchleyPark: We usually have jobs too, so yes saturdays are fine, thank you for taking the time today bkoep
[12:22 PM] formula350: Might be due to it being The Man's office hours lol But yes, it seems Sat IS a better day. However, I can appreciate the others not quite wanting to use an hour of their saturday for 'work'.
[12:22 PM] HuubR: Thanks, bkoep
[12:24 PM] jeff101: Yes, thanks bkoep.
[12:24 PM] bkoep: That's good feedback to hear that Saturdays are convenient!
[12:24 PM] bkoep: I think we will still continue to shuffle Office Hours a little bit to try to accommodate different schedules, but maybe we can start including more Saturdays
[12:25 PM] bkoep: Thanks all for the great questions!
[12:25 PM] formula350: So yesterday I came across a curious instance where scientists modified Leucine tho mimic a Methionine without the Sulphur (I presume; it was to 'prevent oxidation'), which this was called Norleucine. I wonder if something like that could be done to Cysteine, too, to give us an extra sidechain to work with... (feel free to field this if you want bkeop lol)
[12:26 PM] BletchleyPark: I'm off now, good night
[12:26 PM] formula350: Cya Bletchley
[12:27 PM] robgee: Bye Bletchley, Thanks bkoep
[12:29 PM] bkoep: @Formula350 We like to stick to the 20 canonical AAs as much as possible. Mainly because they are easy to test (just about any organism in the world can translate a protein made from the 20 AAs). If we started incorporating non-canonical AAs, we would have to use specials modified E. coli to test them, or else synthesize them chemically. That makes testing more difficult.
[12:29 PM] formula350: *snaps fingers* Drat. :P Thanks though :D
[12:30 PM] Jumper2: After getting into playing Foldit, I've found that I also enjoy just browsing around the PDB database looking at interesting structures. One thing I've noticed is that the so many of the biological proteins have "bad" aspects to them from what might be a score perspective. Just viewing a few, the categories of "outliers" is impressive (Ramachandran, Rotamer, RSRZ, Angle, RSRCC, Mogul-angle, Mogul-bond). And many natural proteins seem loaded with these outliers. So questions like alcor29's about what is an expected "red flag" that could be ignored versus a genuine issue really help us out in trying to get a handle on finding solutions. One thing that might be useful would be to load some sample PDB proteins into Foldit puzzles just so we could see how they show up in the score and various objectives. I think that would go a long way towards improving our qualitative grasp on what things we really need to concentrate on.
[12:32 PM] formula350: Jumper, press keyboard Up Arrow. press CTRL+A, then CTRL+C. Go to #bugs-and-feedback. Press CTRL+V, hit ENTER lol (I support that idea, though)
[12:42 PM] pc: for the Goodhart's Law, yo avoid this problem, banks use simulators that have lot of parameters to make good economic predictions. The Goodhart's Law is not a measure that is too much accurate, it is just that we use too much only one.(edited)
[12:50 PM] bkoep: @Jumper2 That's a great observation about imperfections in PDB structures, and I'll chime in that there are at least two important caveats to consider here: 1. Poor quality models It is not trivial to build a protein model from experimental data (X-ray diffraction, cryoEM, etc.). If the model builders are not very careful, it is easy to over-fit your protein model to noisy experimental data. This can lead to outliers in PDB models that are probably errors, and do not actually reflect the true structure of the protein. 2. Natural proteins are non-ideal We should expect natural proteins to have some non-ideal features -- not because they represent good design principles -- but because they can get away with it. Natural proteins are not optimized for folding stability, but for organism fitness (via natural selection). So many natural proteins are right on the boundary of folding stability. Furthermore, they are not optimized rationally, but "accidentally" over billions of years of random mutation. For protein design purposes, we are most interested in discovering robust design principles that can be used to rationally design a protein in minutes/hours. This is maybe a reason to be cautious about how much we guide to nature in the field of protein design.(edited)
[12:52 PM] Jumper2: Definitely good information, thanks! I'm guessing #1 is why there's the validation section prominent on the front page (the red to blue bars)
[12:53 PM] pc: yes interesting. In foldit we try to create clean and safe proteins, to make sure they work ^^(edited)
[12:54 PM] formula350: Which I think highlights exactly why people shouldn't go out of their way to look up a Nature made protein on PDB to get its sequence and try to recreate it for a design in Foldit, since your results likely won't produce the intended results. (Or if it does, in Foldit, it stands to reason that it may not in the wet lab)
[12:57 PM] Jumper2: Agree on #2 as well. It seems that one of the big questions we (the planetary we) need to answer is that if we limit our designs to stable, robust constructions that can be relied upon, have we excluded certain types of functionality because those are inherently only possible within the domain we're trying to avoid.
[12:58 PM] Jumper2: An answer to that question would be nice to have sometime in the next half century
[12:59 PM] Jumper2: Thanks for taking the time today to answer our questions!
[1:01 PM] formula350: the extended time, at time

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hours 11/5/20- Led by beta_helix and sethcooper

6:05 PM] beta_helix: Hi everyone! We'll start today's Foldit Office Hours very soon.
[6:05 PM] formula350:riggety-REMIIIXXX *airhorns blare*
[6:05 PM] pc: hi
[6:06 PM] beta_helix: Hello everyone. I'm here with Seth Cooper (the co-creator of Foldit) for Foldit Office Hours!
[6:06 PM] sethcooper:hello!
[6:06 PM] formula350:beta_cooper in the house.
[6:06 PM] jeff101: Hi! Thanks for coming
[6:07 PM] beta_helix: Thank you for stopping by
[6:07 PM] Todd6485577: Happy Folding all
[6:08 PM] formula350:Well I guess I'll jump in and ask either one of ya: What's the chances we'll ever get more Building Blocks for Blueprint mode?
[6:09 PM] Todd6485577: Or like customized building blocks, like select segment save as building block?
[6:10 PM] sethcooper:I think we have discussed improving them
[6:10 PM] sethcooper:I'm not sure about saving existing segments thought!
[6:10 PM] sethcooper:that sounds useful
[6:11 PM] beta_helix: We've talked about adding a much wider selection of loops and building blocks...
[6:11 PM] formula350:Yes, I have that in my Feature Request document for the Devs. The ability to save our own blocks, of even larger designed portions. (Only ones that have "passed" filters though)
[6:11 PM] JohnMcLeod: oh joy :-)
[6:11 PM] beta_helix: and hopefully this is something we could get to in the not too distant future.
[6:11 PM] alcor29: 1. What is the thinking behind doing a MERS binder? 2. What is the thinking behind exploring that 2 corona binders linked together is berrter than one?
[6:12 PM] pc: Why there is no sars-cov2 binder design puzzles anymore ? will there be other later ?
[6:12 PM] formula350:Thanks, I'm glad to hear it's been discussed :)
[6:13 PM] beta_helix: @pc I believe the IPD team wants to do more analysis on your sars-cov2 binder design puzzles first, before posting more of them.
[6:13 PM] pc: thanks
[6:13 PM] milkshakeiii: 1912b is technically sars-cov2 right?
[6:13 PM] milkshakeiii: with two spikes
[6:14 PM] formula350:Yes, and LCB1 and LCB3 designs that we're trying to "link" together.
[6:14 PM] beta_helix: Similar to the addition of metrics, first and foremost we want to make sure that all of your effort yields as promising structures as possible
[6:14 PM] jeff101: I think there is something wrong with the LUA commands save.LoadSolution() and save.LoadSolutionByName(). I wrote a Feedback about it:
[6:14 PM]
jeff101: https://fold.it/portal/node/2010726
[6:15 PM] jumper2: A recent puzzle mentioned that loops would be penalized if they didn't match one of the available building blocks. Unfortunately it didn't specify "match" Would a helix-helix block that was Red,Green,Blue,Blue,Red count as match or do the Rama angle have to be within some defined but unpublished epsilon of what the building block uses?
[6:15 PM] zo3xia: I shared a new update. Doesn't seem to freeze foldit
[6:16 PM] pc: Do we know why proteins have more chance to works in lab with SC > 0.6 in design puzzles ?
[6:17 PM] sethcooper:I'm not totally sure why those functions might be missing solutions
[6:18 PM] sethcooper:it looks like they should have a solution at index 0 though
[6:19 PM] beta_helix: @alcor29 (Re 1) The idea with the MERS puzzles is that it would be extremely useful to generate a successful solution to this. Obviously this is the case for any disease, but with MERS it is so similar to covid, that you already have a ton of experience tackling this type of topology.
[6:19 PM] Todd6485577: I would guess because the SC factors into account parts of the overall shape that would be formed once it is bound.
[6:20 PM] alcor29: k
[6:21 PM] Todd6485577: but tat's just my guess
[6:22 PM] beta_helix: @Jumper2 can you tell me which puzzle that was?
[6:22 PM] jumper2: Let me see
[6:25 PM] pc: (For the SC question, it is more why it is 0.6 and what happen in reality)
[6:25 PM] donuts554:Why is there a cluster of oxygen atoms on one side of the locked and unlocked part in the Aflatoxin Challenge puzzle?
[6:25 PM] donuts554:https://fold.it/portal/files/chatimg/irc_902783_1588135313.png

[6:25 PM] Ridick051: what is the plan for the future of foldit? where is the journey going?
[6:27 PM] sethcooper:something we have been thinking about for a while is VR
[6:28 PM] jumper2: for the building block challenge look at 1913 even, it's in the first comment section by bkoep under "Ideal Loops"
[6:29 PM] beta_helix: @alcor29 (Re 2) I believe the spikes that were bound the design from the IPD were trimers: https://science.sciencemag.org/content/sci/370/6515/426/F4.large.jpg

[6:30 PM] jumper2: The SARS-CoV-2 spike protein is definitely a trimer of RBD's. I believe they can open and close independently
[6:30 PM] beta_helix: But rigid linker design is a super tough problem in protein design, so the first step is to work with 2 copies of the spike.
[6:30 PM] formula350:Jumper, I suspect that it's a simple wording snafu. As you notice, on a number of the puzzle's for his Objectives explanations, he actually words the one for SS Design as "Penalizes for CYS", when in fact CYS is always disabled.
[6:30 PM] formula350:(the one time he forgot to post that, I posted it and corrected that, which it looks like he might've copy-pasted that one since 1913 has it correctly worded as "Disabled" heh)
[6:31 PM] beta_helix: We are very exciting about these Designable Linker Puzzles (can I call them DLPs? ) because this is clearly something that computers have a lot of trouble with...(edited)
[6:31 PM] alcor29:Thanks beta_helix:.
[6:31 PM] beta_helix: ...and hopefully they are fun to work on!
[6:32 PM] Ridick051: yes it is ^^
[6:32 PM] Skippysk8sIRC: new shiny toy
[6:32 PM] Susume: @Jumper2 I can't remember if loops are evaluated on phi,psi or on rmsd to the building block, but I do know you can be in the right abego colors and not be close enough to the target shape to get credit for the loop
[6:32 PM] formula350:Not us human computers, we'll do to it like we did with the... what was it, Monkey Virus or AIDs, in which we solved in a couple weeks what had stumped scientists for 15 or so years lol
[6:33 PM] beta_helix: The Contenders actually solved it in less than 10 days
[6:33 PM] jumper2: If you're binding to one of the RBD's while it's extended, and the virus can retract them to prevent detection by the immune system until it's in a more favorable environment (temp, pH, etc.) then by using a DLP, do you have to have two extended for it to bond? That seems like it would be worse since any virus with 0 or 1 extended would get a pass through
[6:33 PM] alcor29: DLPs it is!
[6:33 PM] jumper2: Thanks @Susume
[6:34 PM] jumper2: Or if a DLP bound to a virus with one RBD extended, could it possibly jam a second one closed?
[6:35 PM] jumper2: Given the symmetry of the trimer, if you had a single copy of LCB1 or LCB3 to bind to a single extended RBD, then had some "extra junk" hanging off of it that could jam the two other RBD's in the down position
[6:36 PM] beta_helix: Seth, are you an expert on DLPs? I certainly am not, but my guess would actually be that this is a relatively new field and we probably don't have that many cases of them working. (This is totally speculation on my part!).
[6:36 PM] beta_helix: I believe the team was planning on having a specific chat on DLPs (with those who created the puzzle)
[6:37 PM] formula350:I suspect that with how many "Spikes" there are on the whole virus, as well as how much of the DLP would be injected into us, that the chances are good for enough of the domains to be open.
[6:37 PM] jumper2: It just seems from the literature that it might be common to find a virus with only one extended RBD (or maybe that's just how people like to draw the thing)
[6:37 PM] Skippysk8sIRC: applause
[6:37 PM] beta_helix: Seth, does that sound right? If not, we should schedule that anyway!
[6:37 PM] formula350:There's a blog post about the DLP, it's just a primer though.
[6:37 PM] sethcooper:yeah it seems worth having a specific chat about those
[6:37 PM] beta_helix:
Coronavirus Designable Linker Puzzles
Coronavirus Designable Linker Puzzles
[6:38 PM] formula350:For in-game clickers:
[6:38 PM] formula350:https://fold.it/portal/node/2010706
Coronavirus Designable Linker Puzzles
Coronavirus Designable Linker Puzzles
[6:38 PM] beta_helix: Thx
[6:38 PM] formula350:(once Josh's Quality of Life build gets debugged, that won't be a problem, heh)
[6:39 PM] donuts554:Also why is there a cluster of histidine amino acids to one side in the locked and unlocked part of the Aflatoxin Challenge puzzle?
[6:39 PM] beta_helix: @donuts554 I was just about to answer you
[6:39 PM] alcor29: Out of left field: Is anyone working on trying to do a Cas9 (CRSPR) attack on the cov-sars-2 DNA?
[6:39 PM] beta_helix: I'm looking at your screenshot...
[6:40 PM] jumper2: It would be nice to know how the DLP's react under specific circumstances. Looking at the screen where one's thumb is about an angstrom long, there is a mental model that is easy to fall back on of treating everything like levers and boards attached with string and normal non-quantum stuff. But would a DLP actually act like a monkey wrench thrown into the bearings of a steam turbine or would it act like a mote of dust. Good to understand the order of magnitude of these interactions
[6:43 PM] Susume: @alcor29 cov-sars-2 is an RNA virus (no DNA) - I think CRISPR for RNA is still very new.
[6:43 PM] beta_helix: @donuts554 I've been staring at that screenshot for a while and I don't see an crazy unusual amount of HIS there
[6:43 PM] jumper2: Another interesting application of DLP's would be if you could choose bonding sites that are conserved across mutations and have the middle stuff "over span" the area that sees all the mutation churn that confuses the immune system
[6:44 PM] beta_helix: (I counted 3 towards the bottom?)
[6:44 PM] alcor29:Thanks Susume.
[6:44 PM] beta_helix: That would be sweet though!
[6:47 PM] jumper2: Both measles and influenza are RNA viruses that mutate so fast they become almost a swarm of cousins. But the site the immune system binds to on measles doesn't change (or when it does the virus is not viable), but influenza just churns. But a DLP shaped like a horseshoe magnet could connect to points that don't change making some sort of super-stretch anti-bodies
[6:48 PM] donuts554:There are 6 histidines here
[6:48 PM] donuts554:IMAGE: http://fold.it/portal/files/chatimg/irc_902783_1604627324.png

[6:49 PM] beta_helix: Thanks donuts, I've been staring at zoom meetings all day. This helps!
[6:49 PM] formula350:That's not a very good screenshot to display them Donuts, since 2 of them are vertically viewed.
[6:50 PM] beta_helix: (although I keep trying to rotate your screenshot!)
[6:50 PM] formula350:We all do that Beta T_T Thus my request for our screenshots to be MOLs lol
[6:50 PM] beta_helix: Josh, you're totally on that, right?
[6:51 PM] sethcooper:there are also some updates to the blog post on metrics:
[6:51 PM] sethcooper:https://fold.it/portal/node/2010472
Introducing Foldit Metrics
Introducing Foldit Metrics
[6:52 PM] formula350:(apparently jflat has something in the works for us to view our proteins on the website using a MOL viewer, but the impression I got was it won't be screenshot related... time will tell!)
[6:52 PM] beta_helix: @formula350 jflat totally does, but I think that won't be until after the new website is up and running
[6:53 PM] formula350: Yea :(
[6:55 PM] beta_helix: @donuts My guess is that those are oxidized histidines, but I will check with UC Davis and post their answer in our post-Office Hour thread: https://fold.it/portal/node/2010531
[6:56 PM] formula350:https://fold.it/portal/node/2010531
[6:57 PM] donuts554:How do you think those clusters contribute to the aflatoxin enzyme's function?
[6:58 PM] beta_helix: are there any final questions for Seth or I? We will try to setup a Designable Linker Puzzles (DLP, copyright beta_helix: 2020) chat with neilpg628 very soon... probably after looking over the results of the first puzzle.
[6:58 PM] formula350:Something I've been trying to ask at Office Hours lately: What is one of the most common things you see us doing with our designs that either: you wish we would cut back on -or- you think is really interesting and would like it if more of us did it? (your choice; answering both is always welcomed lol)
[6:59 PM] beta_helix: @donuts that would be my guess, but I want to get you a proper detailed answer from the experts... plus he was a homie of mine when we were both in the Baker Lab
[6:59 PM] beta_helix: @formula350 Yes, I remember you always ask that, but totally I think I have a decent answer for you!
[7:01 PM] beta_helix: Now that we have the new metrics (that everyone loves ) in our mind those solutions are already useful. ie you don't need to keep grinding on them.
[7:01 PM] Skippysk8sIRC: you do know we play the last day for fun and group bragging rights. Is there anything more fundamental
[7:02 PM] beta_helix: Ideally, we'd love it if once you create a model that "satisfies all the metrics" you completely forget about that topology and come up with a brand new one from scratch!
[7:02 PM] formula350:In other words: "Don't End Game Your Designs Please"
[7:02 PM] beta_helix: @Skippysk8s I know but formula350 asked!
[7:02 PM] jumper2: produce a miracle, rinse, repeat
[7:02 PM] beta_helix: there you go! easy as that!
[7:03 PM] formula350:Mommy said I'm her little miracle ^_^
[7:03 PM] Skippysk8sIRC: ha ha. If there is feedback you can share, either positive or negative, we'd appreciate it
[7:03 PM] beta_helix: Why are we so picky? Because you all know the success rate in the lab for designs...
[7:03 PM] beta_helix: so even though your Foldit score might beat everyone else... it might totally crash out in lab
[7:04 PM] formula350:I think that's why we need more "Hand Fold" puzzles. I'm not sure why those went extinct :\
[7:04 PM] beta_helix: but if you generate 100 models that "meet the metric criteria" then that increases the odds A LOT
[7:04 PM] beta_helix: Seth, why did we stop those!?
[7:04 PM] jumper2: And it also seems like you want structure and repeatability and not a "just works by chance" like what evolution comes up with. Eventually, you want to bring out a protein kit. Hence the support for recipes
[7:04 PM] alcor29: So is anyone trying to figure out how to reward that behaviour: Giving up score to design another one?
[7:04 PM] Skippysk8sIRC: agreed. If possible, try to stagger end time for big puzzles so we can work on one by hand, put on recipes for game while we work on the other. I can't work 2 big puzzles at the same time
[7:04 PM] beta_helix: Especially for design, which I always saw as a lot more hands on (compared to running mutate forever)
[7:05 PM] jumper2: Because with recipes, we explain our logic for a repeatable process
[7:05 PM] beta_helix: @Skippysk8s very good point... we don't want to bring back any CASP memories (for those who survived those days)
[7:05 PM] Skippysk8sIRC: do you want us to share our "bomb" scores that might be ok
[7:05 PM] formula350:Ok this is an important followup to what you've said: If you'd like us to stop once we hit a good metric... What if we've done so under a Clash Importance of 0.40? In real life won't that want to relax more? So, shouldn't I work on it at a higher CI after, before submitting the design?
[7:06 PM] beta_helix: @Jumper2 that totally makes sense... but what if that logic has a flaw, and you might discover a better logic manually?
[7:06 PM] Dudit: Is it possible to combine DDG, SASA, SC into One Single Metric?
[7:06 PM] jumper2: New version of a recipe or a completely new recipe
[7:06 PM] beta_helix: @Skippysk8s honestly: if they don't meet the metrics, they almost have no chance of working in the wet lab
[7:07 PM] Skippysk8sIRC: no, I mean lousy score as it wasn't worked at higher wiggle
[7:07 PM] jumper2: The recipes are based on what we discover by manual folding
[7:07 PM] beta_helix: @formula350 that is a good point... you could also make a garbage structure with decent metrics, and we don't want that. Again: we're only asking for perfection here, what's the big deal?
[7:08 PM] donuts554:Not all of the recipes
[7:08 PM] jumper2: Recipes are genetic plasmids in a sea of stinky bacteria all trying to get the best score
[7:08 PM] formula350:hahah
[7:08 PM] Enzyme2: Ihate endgaming more than anyone. But I like points more
[7:08 PM] robgee: points are my metric ;p
[7:08 PM] sethcooper:possibly metrics could be combined
[7:08 PM] beta_helix: @robgee and Foldit is a game, so it should be!
[7:08 PM] sethcooper:but is it more useful to see them separately?
[7:09 PM] alcor29: So the recommended metric scores are absolute minimum reqs?
[7:09 PM] beta_helix: We're honestly been discussing different ways of incentivizing what I've been talking about, because it's obviously not straightforward.
[7:09 PM] formula350:I guess my quesiton more was: is a fully-mutated and worked out solution at 0.40 CI still viable, or is wiggling at 1.0 a must?
[7:09 PM] Skippysk8sIRC: many of us try the science first. Then we play for fun, points and bragging rights
[7:09 PM] beta_helix: @alcor29 Yes, for sure... without any other problems with the model too!
[7:09 PM] jumper2: I like as much stuff separate as possible.
[7:10 PM] beta_helix: @Skippysk8s which is what the Share with Scientist button is for!
[7:10 PM] jumper2: More information display in densest form. Otherwise you might as well just have the top score and tell everyone if you want more detail that's what the "tab" key is for
[7:10 PM] Skippysk8sIRC: I do that... and label junk accordingly ;)
[7:10 PM] beta_helix: Nobody is going to stay with Foldit if you're not having fun... so we never want to take that away!
[7:10 PM] Susume: @formula350 low CI lets things get closer together, so I'd be worried that the metrics might not hold when wiggling at 1.0
[7:11 PM] donuts554:How would the the Foldit score function look like if it was put in terms of the fundamental constants of this universe?
[7:11 PM] alcor29: How about the scores not postable if the metrics aren't met?
[7:11 PM] Skippysk8sIRC: hardball :)
[7:11 PM] beta_helix: @Jumper2 exactly.... we don't want to make the metrics a black box
[7:11 PM] formula350:We use it don't worry lol We've actually had to request the amount of solutiosn we can Share be INCREASED, since we've been making so many that we've ran out of slots lol (They have been increased though, so no worries. I think we're able to each upload 15 now, instead of 5)
[7:11 PM] sethcooper:I think I need to head out now
[7:12 PM] Skippysk8sIRC: don't do that to beginners
[7:12 PM] beta_helix: Thank you, Seth!
[7:12 PM] sethcooper:thanks everyone!
[7:12 PM] formula350:Thanks Seth, and Beta. Sorry for keeping you longer :}
[7:12 PM] Skippysk8sIRC: Thanks Seth
[7:12 PM] donuts554:You are welcome!
[7:12 PM] Skippysk8sIRC: Thanks Beta
[7:12 PM] Susume: hold up, Rosetta energy units aren't the fundamental constants of the universe? darn!
[7:12 PM] Dudit: How about gradual New Metrics points?
[7:12 PM] Enzyme2: if a player creates several design puzzle solutions. How many of those do you actually see?
[7:12 PM] formula350:@Dudit 1913 has that!
[7:13 PM] robgee: Thanks Seth and beta_helix:
[7:13 PM] jumper2: Thanks!
[7:13 PM] Skippysk8sIRC: Enzyme, I think we have to share one of each with scientists to be sure. It need not be end gamed all the way through
[7:13 PM] Dudit: Thank you
[7:13 PM] beta_helix: @Enzyme2 we see all the Share with Scientist solutions All of them! (even the junk-labelled ones)
[7:14 PM] donuts554:Yes but how would the equation to calculate the Foldit score function look like if it was put in terms of the fundamental constants of this universe?
[7:14 PM] formula350:Agreed Susume. I think that's what I was slightly curious to make sure of. Mainly trying to determine if designs I run out of time on, since I fold at 0.40, if I should bother to share it. By the sounds of it: No, it wouldn't be worth it, since it'll not be producible in real life.
[7:14 PM] Enzyme2: so if it's isn't shared, you'll only see the top solution. got it.
[7:15 PM] beta_helix: @formula350 exactly... The wet lab is at CI = 1.0
[7:15 PM] jeff101: https://fold.it/portal/node/988112#comment-28798
[7:15 PM] beta_helix: @Enzyme2 in general, I think this is a fair statement... though that depends on the puzzle, of course
[7:15 PM] jeff101: maybe rmsd dot plots of each player's solutions would encourage more diversity of solutions
[7:16 PM] donuts554:Maybe there could be an all loops challenge where there cant be any sheets or helixes in the protein
[7:16 PM] beta_helix: Does anyone remember the Exploration Map?
[7:17 PM] Skippysk8sIRC: yes. It was easier than CASP
[7:17 PM] beta_helix: Hahahahahhahahahahaa
[7:17 PM] beta_helix: It started sucking up a lot of memory, though!
[7:17 PM] formula350:We have plenty of spare (computer) memory these days.
[7:18 PM] Skippysk8sIRC: so try totally different structures for you if possible
[7:18 PM] formula350:Bring back Exploration klthnx<3
[7:18 PM] alcor29: I still think the obvious is: If metrics aren't met the scores are not valid.
[7:19 PM] Susume: donuts our designs really have to have SS in order to fold up. Nature can get away with long loops but we can't
[7:19 PM] formula350:Honestly, I'm... onboard with that Alcor!
[7:19 PM] Skippysk8sIRC: need new players alcor29. Though I agree that after a while your suggestion is fair
[7:19 PM] beta_helix: Ok gang, I gotta go... (I just saw your "fundamental constants of this universe question", donuts! I don't know if I can ask around for any answer on that one... but I'll try)
[7:19 PM] Susume: thanks beta
[7:19 PM] alcor29: Yeah but those players usually give up anyway. Maybe/
[7:19 PM] formula350: Skippy, Metrics aren't a part of the BEginner puzzles, so that won't scare off newbies.
[7:20 PM] alcor29: Thanks beta
[7:20 PM] Dudit: Thanks @beta_helix
[7:20 PM] beta_helix: @alcor29 it might be a different type of puzzle, like a Boss Level or something.
[7:20 PM] Formula350: Thanks Beta. Try to get our Hand Fold puzzles back lol
[7:20 PM] alcor29: Hahahaha
[7:20 PM] jeff101: thanks beta
[7:20 PM] Skippysk8sIRC: Thanks Beta. We do need to let our new players get some reward or see some progress as they move to the regular puzzles
[7:20 PM] alcor29:Thought that might work. Having another review level.
[7:20 PM] beta_helix: I'll bring up hand puzzles for sure, I always loved those... maybe we can make them last 1 month, so there is no time pressure.
[7:21 PM] beta_helix: Thanks again everyone, keep up the great folding!

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hours 11/15/20: led by Neilpg628

pre-office hour
11:39 AM] : HuubR: Question for Neil: What is the most important aspect of the linker: just to keep the two binders at a fixed distance, or also to make sure their orientation stays the same (relative to each other). In other words, when the binders can pivot around the ends of the linker, is that good or bad?
[11:39 AM] jeff101: yes, thanks Ariana. Have a good weekend.
[11:40 AM] HuubR: Yes, Ari, thank you for spending time on a Saturday morning.
[11:46 AM] jeff101: I put zero length bands of strength 10 in the non-mutable part of 1918b to keep them in place.
[11:46 AM] ZeroLeak7: results of the last rounds of the MERS-CoV Binder Design in the lab?
[11:46 AM] jeff101: I use the reset puzzle pose as a Guide to make sure things don't move.
[11:47 AM] ZeroLeak7: yes but the clashes are there
[11:47 AM] jeff101: It makes building the linker more predictable, but maybe we are supposed to let things move more freely.
[11:48 AM] jeff101: if I omitted the zero length bands, would the clashes go away?
[11:48 AM] ZeroLeak7: no it's on the locked lcb1 binder
[11:50 AM] jeff101: so we are stuck with the clashes that are in the non-mutable parts, right?
[11:50 AM] ZeroLeak7: yes
[11:50 AM] ZeroLeak7:
[11:50 AM] donuts554: hello
[11:51 AM] jeff101: hi donuts
[11:51 AM] ZeroLeak7: hi
[11:51 AM] Todd6485577: Morning, well afternoon everyone.
[11:51 AM] ZeroLeak7: hello todd
[11:52 AM] donuts554: hello how are you?
[11:53 AM] ZeroLeak7: I'm fine thank you and how are you?(edited)
[11:53 AM] Todd6485577: Doing alright, working on A+ cert stuff and three puzzles.
[11:53 AM] Todd6485577: Hows everyone else doing?
[11:54 AM] donuts554: I am good, thanks for asking!
[11:54 AM] ZeroLeak7: yes I'm doing great on the all 3 puzzles
[11:54 AM] Todd6485577: also running powershell cipher command on my work computer to scrub all my deleted files
[11:55 AM] ZeroLeak7: are you in gargleblasters now :)?
[11:56 AM] Enzyme2: I think he just needs to restart Foldit
[11:56 AM] ZeroLeak7: ok
[11:56 AM] Todd6485577: Yeah, just joined it today. Needed to be able to see more activity to eveolve.
[11:56 AM] Enzyme2: shows him on the website, but not in yhe group chat
[11:57 AM] ZeroLeak7: gratulations
[11:58 AM] Todd6485577: I'm doing alright on the three puzzles, I'd like to see others solutions so I could be better...hence the group change. I'm pretty sure that I was almost the only one active in hold my beer
[11:58 AM] ZeroLeak7: I bet enzyme could show you some new things
[11:59 AM] Todd6485577: Enzyme, you, formula, I notice who's been active in vet chat
[11:59 AM] ZeroLeak7: there are great players with a great knowledge
[11:59 AM] donuts554: Why is there a Residue Limit on the number of residues in 1918b?
[12:00 PM] Enzyme2: All I do is shake and wiggle
[12:00 PM] Todd6485577: I mutate and wiggle


[10:59 AM] neilpg628: Hi all, its neilpg628 ready to answer any questions about Designable Linker Puzzles, and really any other questions about Foldit!
[11:02 AM] HuubR: Hi Neil
[11:02 AM] neilpg628: Hello!
[11:04 AM] HuubR: I certainly hope it's not just the two of us, but I'm glad you could make it today.
[11:05 AM] neilpg628: People should be dropping in soon Do you have any questions?
[11:05 AM] donuts554: hello
[11:05 AM] HuubR: And yesterday, it was good to hear that you were OK, it was just your car that let you down :-)
[11:05 AM] pc: In linker puzzles, to have something less flexible, is it interesting to maximise interactions (boud, hydrphobics) between the linker and the 2 binders in gray ? Like create a helix near one of the binder helix ?
[11:06 AM] donuts554: Why is there a residue limit on the linker?
[11:06 AM] pc: hi ^^
[11:06 AM] donuts554: hello how are you?
[11:07 AM] neilpg628: @pc Maximizing interactions between the linker and binders is definitely something to have, since that helps provide rigidity to the structure. There were some designs that had this from previous puzzles that we are computationally analyzing
[11:08 AM] neilpg628: The residue limit is primarily to prevent slowdown in Foldit. The current puzzle is one of the largest we've ever had (max length=250) and even though much of it is locked, we don't want to make the puzzle unplayable
[11:08 AM] pc: thanks. In 1918b there is some limitations. We can't create an helix here for exemple, because the 77 sidechain isn't changeable and make clash. http://fold.it/portal/files/chatimg/irc_959223_1606053501.png(edited)

[11:09 AM] pc: Maybe an extended helix here can be interesting to create something less flexible after.
[11:09 AM] pc: (clash, not crash ^^)
[11:10 AM] HuubR:https://fold.it/portal/files/chatimg/irc_959223_1606053501.png

[11:10 AM] HuubR:(for in-game chat)
[11:10 AM] neilpg628: @pc I think that is a valid concern. Originally we did leave the sidechains on the binders unlocked, but that caused slowdowns from the sheer numbers. Possibly we could let only some be flexible for this reason All of the frozen bits are directly from experiments done in the IPD, so those are real results
[11:11 AM] HuubR:So if I understand you correctly, the task of the linker is not just to keep the two binders at a fixed distance, but also to make sure their orientation stays the same (relative to each other). Is that correct?
[11:12 AM] donuts554: Oh yes the orientation too
[11:13 AM] neilpg628: Yes HuubR, that would be ideal. Both of the binders bind to the SARS-CoV-2 spike extremely well, but if we could link them rigidly, we would automatically have a much better binder(edited)
[11:13 AM] neilpg628: The way they are currently oriented matches how they would be in real life
[11:14 AM] HuubR:That's a clear answer. But I have been wondering if there is any way in which we can assess how rigid a particular design is?
[11:16 AM] neilpg628: That would be done on our end, there is no one metric for 'rigid' However, things with good secondary structure, packing, ideal loops, etc (In general things that give a good score) are better contenders
[11:17 AM] HuubR:Can you give any feedback on what we produced in the first rounds, or is that too early?
[11:18 AM] HuubR:(I know that this is a new type of puzzle for all of us :-)
[11:18 AM] donuts554: Should the linker protein be mostly in the concave side of the two locked parts, or be mostly in the convex side of the two locked parts?
[11:20 AM] neilpg628: The convex side seems more likely, since you have more space, but honestly its up to you! There simply is not much data on these types of design problems
[11:22 AM] neilpg628: Also HuubR, we have looked quite a bit at the first two, and I would say that the best designs tend to have a lot of interaction between the linker and the binders (since this helps maintain a fixed structure for the linker) Some of the top structures have a-helices on the linker that form hbonds with the residues on the binder
[11:22 AM] pc: Is it a problem if our linker make some bonds with the virus ?
[11:24 AM] neilpg628: Probably not, though it might be hard to say without more rigorous testing. We would want the linker to behave the same regardless of the virus presence though, because the LCB1-linker-LCB3 complex should act as an independent unit
[11:24 AM] pc: thanks. Are hydropholic bouds in our linker are strong enough to have something less flexible, or hydrophobics interactions are more interesting for that ?
[11:26 AM] neilpg628: @pc I'm not sure if I follow? Generally we would expect that the core remains mostly hydrophobic
[11:27 AM] susume: would it possible to place the boundary between locked and movable residues at a pair with good helix dihedrals? - then we could continue the helix or switch to loop
[11:28 AM] nspc:IMAGE: http://fold.it/portal/files/chatimg/irc_959223_1606069682.png

[11:28 AM] neilpg628: @Susume We actually discussed this on Thursday, and will be doing this for the next puzzle!
[11:28 AM] susume: cool, thanks!
[11:28 AM] nspc:(I am pc) I mean this kind of bouds maybe are too much flexsible and we have to make more hydrophobics interactions instead
[11:29 AM] neilpg628: I think that looks fine as is
[11:31 AM] pc: thanks, so hydropholic networks can be enough to have something strong in some parts (and not too much flexible)
[11:32 AM] donuts554: But I think the hydrophillics want to be around water
[11:32 AM] pc: so it can be less stable than hydrophobic if they want to do boud with water instead ?(edited)
[11:34 AM] neilpg628: @pc Hydrophobics are good for the core, since they allow for a core that actually folds (since hydrophobics want to interact with eachother more than water) Hydrophilics would be good for making hbonds with other residues and water
[11:39 AM] pc: ok thanks. So hydrophobics are mostly here to help the folding. And hydropholics with bonds keep the structure strong.(edited)
[11:40 AM] pc: Is a too long helix is too much flexible ?
[11:41 AM] donuts554: Can the two locked binder parts be independent at first, and then can they rigidly bind to each other and form a disulfide covalent bond on the inside center of the binding site which cant be destroyed, so it still acts like a whole protein at the end?
[11:44 AM] neilpg628: A long helix is not necessarily a bad thing, as long as it is making proper interactions
[11:45 AM] pc: is the main idea of the linker puzzles is to increase contact surface (like sasa) by having 2 binders ? And make it more sticky ? Or there is for other things, like have more chance to find the binding zone ?(edited)
[11:45 AM] pc: thanks
[11:46 AM] Formula350: Just sat down (though did read everything). My quick question before the buzzer: Just curious if the LCB1+Linker+LCB3 will be expressed as a single protein, or if they are intended to be expressed individually and expected to bond as we've designed?
[11:46 AM] neilpg628: donuts554, I'm not sure if there are any disulfides to be formed. If there are no cystines near the binder surface I doubt we could make them, since those binder AA sequences are fixed
[11:47 AM] neilpg628: @Formula350 They would be expressed as a single protein since they are a single AA sequence. We wouldn't be attempting to splice sequences together
[11:48 AM] neilpg628: @pc The main idea is to make a better binder by joining two others. If we could lock the two binders in the correct orientation/distance before binding the resulting protein would have a much higher affinity because the surface area to contact would be much greater
[11:49 AM] Formula350: Thanks. I didn't think so, but I also thought that Aflatoxin puzzle that we were working on was a single chain, but apparently that's a 'ligand'. So finding that out kind of changed my impression of how things could actually be used in the lab vs what we're seeing in Foldit
[11:50 AM] Formula350: Speaking of what pc said, would the CSM Objective be something applicable to the Linker puzzle?
[11:52 AM] pc: @Formula350 for me CSM is only for the part that is in contact with virus, so not very usefull for linker I think. (But it can be usefull if we add part that touch virus maybe..)
[11:53 AM] pc: but, maybe it can be better than void and packing
[11:53 AM] Formula350: Well yes, I suppose what I mean is a modified CSM that was meant to look at only itself.
[11:53 AM] pc: for the linker
[11:53 AM] neilpg628: Do you mean CMS?
[11:53 AM] neilpg628: Contact Molecular Surface
[11:53 AM] Formula350: Contact Surface Metric, the new combo SASA/SC in 1920
[11:55 AM] neilpg628: Oh yeah, CMS is the scientific name That could be useful but we would only add that later as there are still some kinks to work out
[11:55 AM] neilpg628: The Aflatoxin Puzzle does have a ligand, but in this case everything is protein, so that is not an issue
[11:55 AM] HuubR:So if I understand you correctly, the task of the linker is not just to keep the two binders at a fixed distance, but also to make sure their orientation stays the same (relative to each other). Is that correct?
[11:56 AM] HuubR:(Sorry, wrong clipboard)
[11:56 AM] HuubR:I've been looking at the puzzle with what you just told us, about LCB1+linker+LCB3 being a single protein. I would say that the combination is far from being a "globular" shape. Is there a risk that the total protein will not fold like we see it in the puzzle, but rather into something more compact?
[11:56 AM] Formula350: Ah ok, good to know, sorry for the confusion then lol I enjoy the new metrics, as for me, they've been very helpful to create closer to what you all want. So I look forward to being able to use them more (Though I know not everyone does, since older computer are having a tougher time with them)
[11:57 AM] HuubR::D
[11:57 AM] pc: neilpg628, The final protein of linker puzzles look likes an Antibody. Is there some ideas to make something like an antibody later (to be compatible with "phagocyte cells" for exemple)
[11:57 AM] Formula350: I share HuubR's concern and curiosity there, too, which was also partially why I thought perhaps they would be expressed individually, to prohibit them folding properly.
[11:58 AM] Formula350: Err wording. prohibit folding improperly.
[11:58 AM] donuts554: I mean the binder proteins and the linker, not just the binder proteins. I mean can the linker be cut in half, and so one half of the linker tries to rigidly bind with the other half of the linker, and so that a disulfide covalent bond is formed in the inside center of the binding interface of the two linkers, which cant break, so that the two parts could act as one independent protein in end?
[11:59 AM] neilpg628: HuubR, We won't know for sure what anything looks like folded until we make these sequences, but since the binders fold independently into their proper shapes it is unlikely that the whole thing would form a globular cluster
[12:00 PM] neilpg628: @pc These probably wont be used as an antibody, since those are only produced by your immune system
[12:00 PM] HuubR:You mean the binders have strong enough interaction within them to fold as sub-units, and then the whole protein should fold as we see it in the puzzle?
[12:01 PM] neilpg628: donuts554, I can ask about that, it sounds interesting
[12:01 PM] neilpg628: HuubR, That is correct, and we know from experiments that the binders fold as intendend
[12:01 PM] HuubR:Thanks, good to know that!
[12:04 PM] donuts554: Cant there be a dimer puzzle, and the highest working dimers have each protein attached to each of the binders, so they can bind in the end and act as a single protein?
[12:04 PM] Formula350: Yea I think what Donuts is after is closer to the initial test puzzle for linker that we had gotten a number of weeks back, which had twin locked helices, and we had to try to come up with a way to bond them. In that one, the two bundles (and thereby, what we could manipulate) were separate. So my assumption here is that he's hoping we could use CYS to bind and strengthen our linker, by having it be LCB1+half the Linker, and then the other half of the linker+LCB3. (sound about right, Donuts?)
[12:06 PM] donuts554: Yes it sounds about right
[12:06 PM] susume: donuts, disulfides are strong, but don't forget the peptide bonds (the ones that hold two pieces of backbone together) are super strong too, so having it all be a single protein is quite strong - we just have to get a stable shape for it
[12:07 PM] susume: heh, 'just'
[12:07 PM] neilpg628: I can ask about that, but as Susume said, the actual covalent bond between bb residue atoms is as strong as any disulfide
[12:08 PM] Formula350 Foldit Players - We make the Impossible..... a bit more Plausible!
[12:08 PM] susume: +1 plausibility
[12:09 PM] neilpg628: Exactly
[12:09 PM] donuts554: Oh ok, I thought that the linker problem could be solved by attaching a half of a hemoglobin complex/DNA to one binder side and the other half to the other binder side
[12:11 PM] neilpg628: That could get complicated, since we also have restrictions on avoiding the virus
[12:11 PM] neilpg628: Anyway, I think we are good here!
[12:11 PM] neilpg628: It was nice talking to you all!

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office hour 12/6/20: led by Jflat06

[2:22 PM] jflat06: Hey all, I'm here now
[2:22 PM] dudit:: Hi @jflat06
[2:22 PM] jeff101: Yay!
[2:22 PM] formula350: Oh so maybe he was applying Waffle Face like I was going to joke about :D
[2:22 PM] formula350: (sleeping on his keyboard)
[2:23 PM] jeff101: Did you attend the CASP meeting this past week?
[2:23 PM] jflat06: (was in the middle of making grilled cheese)
[2:23 PM] jflat06: I did not
[2:23 PM] jflat06: We talked about it at our meetings, though
[2:24 PM] grogar7: Alphafold sounds like a huge breakthrough
[2:24 PM] formula350: Technically "Alpha Fold 2"
[2:24 PM] dudit: What is the future of Foldit when AlphaFold is capable in Protein Design Puzzle?
[2:24 PM] pc: jflat06 : are LCB1 and LCB3 usefull alone for a medication against covid ? And when they can be usable on humans ?(edited)
[2:25 PM] jflat06: Indeed it does. As a computer scientist (instead of a proper biochemist), I had to clarify with some of the other foldit team as to exactly how much of it was hype and how much was not.
[2:26 PM] spvincent: Amazing achievement though AlphaFold2 is, does it provide any extra insight or understanding of the protein folding process?
[2:26 PM] jflat06: @pc i'm not up to date on the status of the various antivirals
[2:27 PM] jflat06: Probably a better question for a biochemist - my guess is it would still be a while, unless they're already undergoing human trials for safety
[2:27 PM] jeff101: what have you been working on lately that you can tell us about?
[2:28 PM] formula350: Yea, In other words, the best Qs to ask jflat would revolve around the software and tools of Foldit or similar. (As I understand it heh)
[2:28 PM] jflat06: @dudit: We haven't seen exactly what alphafoldit will look like in protein design, but we're starting to think about ways to incorporate it in a way that still leverages humans
[2:28 PM] jflat06: haha, alphafoldit (i can't type fold without the it, apparently)
[2:28 PM] grogar7: lol
[2:29 PM] formula350: Freudian Slip, perhaps... Might be subconsciously answering Jeff's Q.... ;) ;) lol
[2:29 PM] formula350: err jeff101's, since, you are also a Jeff...
[2:30 PM] jeff101: or what do you plan to work on next week?
[2:30 PM] dudit: @jflat06 so Foldit will still exist forever?
[2:30 PM] susume: to what extent has the team talked about adding trRosetta info to foldit? (trRosetta is based on alphafold 1)
[2:30 PM] Josh:
Ooh! susume: I know this one! But I can let jflat answer :)
[2:30 PM] jflat06:
If alphafold really turns out to be an oracle for protein design, the hardest part of folding will shift to accurately describing the problem at hand, so that the neural nets can work their magic on that.(edited)
[2:31 PM] Jumper2:
Someone mentioned Alphafold on Github, who's up for writing the alphafold.lua recipe? LOL
[2:31 PM] jflat06:
So one possibility for the future is to have foldit players design puzzles for a future design-alphafold to work on
[2:32 PM]
formula350: I could also see us still being allowed to then attempt to improve upon what the AF2 designs, to further its own 'knowledge'.
[2:32 PM] pc: jflat06 : Is alphafold team is interested by foldit player solutions database ? (with all solutions we do)(edited)
[2:32 PM] susume: we could design backbones with starting sequences, and alpafold-design could find good sequences for them - because backbone variety and novelty is a foldit strength
[2:32 PM] jeff101: does alphafold work for man-made sequences?
[2:33 PM] jflat06: I think alphafold mostly uses native backbones as their sources for training data
[2:33 PM] jflat06: @susume We're definitely pushing for trRosetta into Foldit - it's an active project!
[2:33 PM] spvincent: Yes, wouldn't Foldit designs likely have no analogues in AlphaFold2s training set?
[2:33 PM] susume:: jeff101 I want to know that too - alphafold 1 worked well on designs, can't wait to hear if alphafold 2 does too
[2:34 PM] jflat06: @spvincent depends on the particular design, but yeah, a lot of foldit designs are fairly novel
[2:34 PM] jflat06: the cool part is if we verify your structure experimentally, it IS a native structure at that point, and could be included in alphafold's model
[2:35 PM] susume:
Newsletter July 3: Initial Reactions
Newsletter July 3: Initial Reactions
[2:35 PM] Jumper2: If both are neural net/AI type efforts, is there a succinct comparison of Alphafold to trRosetta?
[2:35 PM] spvincent: ok, tx
[2:35 PM] susume:reminder of the trRosetta paper showing it works well on design
[2:36 PM] jflat06: I believe trRosetta is based on the original alphafold from a while ago
[2:36 PM] jflat06: the new methods in alphafold2 will presumably be included in an update to trRosetta
[2:36 PM] Jumper2: trRosetta++
[2:36 PM] jflat06: hah
[2:36 PM] Jumper2: with templates
[2:37 PM] jflat06: Anyway - to summarize, we are definitely thinking about neural nets, and how to incorporate them into Foldit
[2:38 PM] jflat06: science/development can be a bit slow, but you should expect to see something in the future
[2:39 PM] jflat06: As for my current work, I am working on getting the client co-operating with the new website. There's a bunch of changes to our server communication protocols that effectively require a re-write of all of our server code. And our server code isn't exactly... modular. It a big old messy hairball 13 years in the making.
[2:40 PM] Jumper2: One idea would be to give Alphafold and the Foldit players the same initial puzzle to see what the solutions are. If the players solutions seem better, then test in the lab. With lab results turn the player solutions into training inputs (both positive for working solutions and negative for those that fail to fold or end up in clumps). Then the foldit puzzles really become meta-puzzles of generating training scenarios.
[2:41 PM] Jumper2: That type of collaboration would seem like it would generate some interesting papers relevant to a wide swath of sciences
[2:42 PM] jflat06: Yeah, there's definitely the potential for producing some training data for a model.
[2:42 PM] jflat06: That's a bit hands-off, though, and it would be far more interesting to have players interacting with design even after AlphaFold has been properly trained
[2:43 PM] formula350: I have 3 questions, and the first 2 are rhetorical: 1) Where's Waldo? 2) Where in the World is Carmen San Diego? 3) If you think of the players like your kids, what is your "proudest dad moment" in your time while working on Foldit?
[2:43 PM] jeff101: do you ever code Foldit LUA commands?
[2:45 PM] jeff101: I'd like to see more related to the Objectives, like list the abego color for each segment, list which segments are in non-ideal loops, have the ideal loops filter depend on the # of residues in non-ideal loops instead of the # of non-ideal loops
[2:45 PM] jflat06: @Formula350 probably when our players discover or create something that makes even our scientists do a double take.
[2:45 PM] jflat06: @jeff101 yup! I think Josh/milkshake have been doing most of the recent work, though.
[2:46 PM] formula350: Doesn't have to be now, but if you happen to have any examples of that, I'd certainly love to hear about some! :D
[2:46 PM] Jumper2: The interesting question is one of what produces good training data. The idea that people and neural nets build up intuition based on repeated exposure to massive amounts of raw experience data. Would training data based on human player intuition be doubly useful for training or would it just end up confusing the AI because of seeming to be too random?
[2:46 PM] dudit: I think it will be great if every Foldit puzzle have a video tutorial in one place
[2:48 PM] jflat06: I do believe we have more to come on at least the objectives. The metrics are very new, and we're trying to make sure we have the right idea before going and giving you lua functions so that we don't have to change them in a way that would break your scripts later on. This is one of the biggest hurdles to writing lua functions.
[2:48 PM] jflat06: @Formula I would definitely have to think about it - I have a terrible memory, so it'd be hard on the spot.
[2:49 PM] formula350: Yep I can relate, if you think about it, I'm always on the Discord :P If not, no biggie!
[2:49 PM] jflat06: @Jumper2 That would be in interesting question in its own right.
[2:50 PM] formula350: That may 'taint' the results dudit:? I think they try to give us any specific "Do this and that" information, beyond what they do now, because they want us to come up with the things they wouldn't have. But I could be wrong.
[2:51 PM] jflat06: Yeah, we definitely like to try and influence players as little as possible going into a puzzle, as we really need as much diversity in the solutions as we can get
[2:54 PM] spvincent: Do you have any particular thoughts on triple helices in that regard?
[2:56 PM] jflat06: (Again, I'm not a biochemist!) I think for our freestyle design puzzles, those aren't always the most interesting. My understanding is that Rosetta does helical bundles well, and foldit players have 'conquered' that type of fold a while ago. However, I believe that in our targeted design puzzles (such as binders for coronavirus), we don't really care if it's some never-seen-before type of foldit - we just care if it works!
[2:58 PM] Jumper2: So what part of Foldit are you spending the most time on as a developer lately?
[2:58 PM] jeff101: more ideas for LUA functions: list blue green or orange for each segment to match the colors you see when you show the Core Existence Objective
[2:59 PM] jeff101: do you know if the Interaction Energy Objective is a good metric for pi-stacking?
[2:59 PM] jflat06: In a way, the freestyle design puzzles (and the nature paper they created) were where we refined foldit and our puzzles so that players could design all sorts of backbones. And now we're starting to try and apply that towards some real world problems.
[3:00 PM] jflat06: @Jumper2 I am working on the new website and associated client updates, as well as general foldit maintenance and tasks.
[3:01 PM] jflat06: @jeff101 I do not. I'm not educated enough on that to be able to say.
[3:01 PM] jeff101: will all the old content be preserved in the new website? like images we have put on the site?
[3:02 PM] jflat06: Most content should be preserved. I can't promise everything, but we're going to try to make it work.
[3:02 PM] formula350: (I'm almost positive this was mentioned in public, which has caused me to waffle with asking but...) The website feature that'd been mentioned once, where we'll be able to use a MOL viewer on the website to look at each others designs... Will that also extend to our shared Screenshots? Or will those still remain as only PNGs?
[3:03 PM] jeff101: will there be a transition period in which both the old and new websites will be online, but the old one will be read only?
[3:04 PM] jeff101: I can't imagine it all working right the first day. What precautions will you take so we can keep playing Foldit and using its website during the transition period?
[3:05 PM] jflat06: @Formula350 We aren't certain on all of the details there at the moment. We would like sharing to be as easy as possible, so you could imagine a 'screenshot' button that would post a link to the model on the website. However, that effectively means that other people could see your raw PDB, atom coordinates and all. So there are some concerns about exactly how this would affect the competition, among other things.
[3:06 PM] jeff101: I sometimes wonder if posting images of our solutions on the Foldit wiki is risky in the same way
[3:07 PM] jflat06: @jeff101 We plan to have a transition time where the old site will be read-only. There will also be a public demo of the website prior to we make the hard-switch.
[3:08 PM] formula350: Yea I had that same exact concern. But then I considered that maybe you guys would be able to use the encrypted file saves you are already, with a modified MOL viewer that'd be able to read them. Then everything is kept 'secret' still. As I'd seen on... one of the sites (YangLab's trRosetta server maybe, or perhaps ZhangLab's CoV-19 info DB) where their Viewer didn't permit the user to view that.
[3:08 PM] MikeCassidytoo: There could br three levels of competitiom: solo, evolver, shared evolver (or some other name)
[3:08 PM] jflat06: Unfortunately using the encrypted solution files isn't really possible.
[3:09 PM] formula350: Locked out most of the functions and even seemed to hide the file's URL behind an obfuscated link (as I'd viewed the page info)
[3:09 PM] formula350: Ah, shame.
[3:09 PM] jeff101: more LUA tools for Objectives: list which reisudes are scoring poorly for the Interaction Energy, and list which ones are doing poorly on the SS Design Objective.
[3:09 PM] jflat06: Whatever the website does to show them to you, they have to end up as a raw PDB at some point, so it would have to decrypt them in javascript right out in the open.
[3:10 PM] formula350: What about using WebGL or CL instead of JS? (which seems to run smoother than JS anyhow)
[3:10 PM] jflat06: webgl is a javascript API
[3:11 PM] jflat06: so your code all is still just code running on the end-user's machine.
[3:12 PM] formula350: hah Did not know that about WebGL! But yea, like I knew we're the side doing the "work" and need the file, I just hoped maybe it'd get stored in memory and need a ton of leg-work to extract.
[3:13 PM] Jumper2: Re: 3d viewer for screenshots Since it's already setup to hide the atom coordinates, it follows that the only viewer that should be able to parse and display the screenshots in 3d would be the foldit game client itself. As mentioned any other viewer will require the unencrypted data in order to render it and you guys have better things to do than write a separate 3d web viewer app on top of everything else. So if you limit 3d screenshots to being viewed in the foldit game client only, then you "simply" (hah, as if writing that makes it so) just add a "read/view only" flag to a game save file. Then 3d screenshots become much like saves. There could be links to them on the website, but the viewing would have to be in the game client. (Similar to recipes listed on the web but loaded into the client)
[3:13 PM] formula350: As, if that's the case, I personally wouldn't care if anyone went through that trouble to copy what I'd done lol (Though a major lab might be another story, however, I thought all of Foldit work taht gets published was basically freely available).
[3:13 PM] jflat06: Possibly. My favored approach would be to try and think about how to design a fair foldit competition framework that wouldn't be harmed by this sort of thing. That way we could really embrace sharing.
[3:14 PM] jeff101: sometimes I try new things on expired puzzles. if I am logged into Foldit, do solutions I generate then still get sent regularly to the server?
[3:14 PM] jflat06: i believe they do
[3:14 PM] jflat06: but it would be rare for us to look at them
[3:15 PM] formula350: Oh, or as Jumper said, bypass the browser and have the Foldit client "view" the solution! Which actually...
[3:15 PM] Jumper2: If 3d screenshots are developed as saves marked read/view only, then they could host other security flags such as limiting the viewer to being within a certain group
[3:15 PM] formula350: Having that capability would go very hand in hand with a feature request which would give us the ability to view our own Saves that way...
[3:15 PM] jflat06: As far as a web viewer goes - there's actually some already written that we have integrated already. So we wouldn't have to write that from scratch.
[3:16 PM] Jumper2: And because they would be read/view only, they shouldn't generate change deltas flowing back to the server or allow people to build their solutions directly on top of that file.
[3:17 PM] jeff101: what if within the Foldit client, there was a but like the Screenshot Camera icon that would rotate the protein around some axis with steps of like 10 degrees and make a gif file movie of the rotating protein?
[3:17 PM] formula350: Yea my thinking is to use whatever it is that the little preview window for Building Blocks has, just in a bigger window like Rama Map.
[3:17 PM] formula350: You probably got that from my suggestion on the Document, jeff.
[3:18 PM] formula350: Sug 1 is a MOL viewer, and falback Sug 2 was a low-FPS, low res GIF (slideshow almost, to keep file size down)
[3:19 PM] jflat06: In any case, we do plan on having a web-viewer for the new website. This is actually a huge request internally among our scientists, as this sort of thing would be invaluable for talking about puzzle results and clearly communicating structures and their strengths/weaknesses to players.
[3:19 PM] jeff101: would posting gif movies on the website be a more secure way to show the 3D structure of our proteins
[3:19 PM] Jumper2: One question would also be whether or not the read only flag would allow recipes to work at all (you could argue that the GetDistance LUA function called on a read-only 3d screenshot save would not be kosher)
[3:20 PM] Jumper2: Now when talking about scientists viewing it, I'm imagining them wanting to look at angstrom level measurements between residues and all the other things for which a full PDB file is needed.
[3:20 PM] formula350: If they open them in a "Building Block Preview" sort of window, which would be overlayed on our screen (sans transparency), there'd be literally no concern about that, since Recipes just flat out COULDN'T work.
[3:24 PM] Jumper2: When considering the detail that scientists might want to see combined with the ease of hitting "share with scientists". That argues for including a very simple way of translating a save to a PDB but that is probably restricted to admin usage only. That would allow "share with scientists" results to automatically be converted to a valid PDB format allowing use of a JavaScript or PyMOL type viewer. They would just have to be cautioned about not saving it in an area reachable by players.
[3:25 PM] jflat06: right, that's roughly our plan, at least for the initial rollout. We have talked internally a lot about how much of these capabilities we want players themselves to have, and we aren't necessarily opposed to the idea of letting players export their PDBs themselves.
[3:26 PM] jflat06: The key is that, if you can export a PDB, we need to ensure that importing one isn't easy.
[3:27 PM] jflat06: but as a first step, this solution-on-the-website thing would be an admin-only tool until.
[3:27 PM] Jumper2: Or if you can export a PDB you should ensure that such a function cannot be called on just any particular save. Thus read-only 3d screenshots would not be exportable, while full player saves might be
[3:28 PM] Formula350: lol Speedy "Proof of concept" (Kept purely internal to Foldit, no web use)

[3:28 PM] Formula350: Whoops Wrong screenshot
[3:29 PM] Jumper2: Import needs to be restricted regardless because it opens up the possibility of being able to use any PDB as a person's own solution.
[3:29 PM] jflat06: yeah, definitely
[3:29 PM] Formula350:

[3:29 PM] Formula350: Thhhat's what it was intended to be lol Dang Photoshop layers
[3:32 PM] Jumper2: But I definitely agree with allowing scientists easy access to player saves in PDB format. As players, IMO, I think anytime we hit the "share with scientists" button, we're in favor of anything that makes it easier for them to evaluate what we are sending them. That would include a lot of the cool features in PyMOL and other viewers they may be familiar with. I definitely would be against hamstringing them to subpar tools.
[3:33 PM] jflat06: just to clarify - all your solutions end up as PDBs in the end. It's just that the current pathway through which that happens doesn't make it easy to dynamically and quickly share these things. We definitely use PyMOL internally!
[3:35 PM] Jumper2: Perhaps in a future version when a client "shares with scientists" the server code automatically translates the save to standard PDB and saves it in a network share that scientists can easily get to with PyMOL or whatever tool they use.(edited)
[3:36 PM] jflat06: that's pretty much exactly what we are doing, lol.
[3:36 PM] Jumper2: As a teacher I once had always quipped "Great minds think alike, and fools never differ."
[3:38 PM] jflat06: haha
[3:38 PM] jeff101: I think the site the FOldit wiki is on will get updated too. Perhaps its address will change.
[3:39 PM] jeff101: When you update the Foldit site, will all the old links still work? Like if you have a bunch of Favorites in your web browser, will their addresses still work?
[3:39 PM] jflat06: the foldit wiki isn't hosted by us, so it shouldn't change
[3:39 PM] jeff101: I think they sent me an e-mail about upcoming changes.
[3:39 PM] jflat06: I think we're trying to preserve old URLs
[3:39 PM] jflat06: ah, ok
[3:41 PM] jeff101: I need to go do other things. Thanks for having this Office Hour.
[3:41 PM] jflat06: Yup, I think I am going to take off too. Thanks for all the questions!

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hours 12/30/20: led by Milkshakeiii

[2:30 PM] milkshakeiii: it's officially office hours time 8)
[2:30 PM] argyrw: ok I left you
[2:30 PM] Dudit: Hi @milkshakeiii
[2:30 PM] argyrw: I hope to see photo of your design
[2:30 PM] Ridick051: yes :) welcome milkshakeiii
[2:31 PM] robgee: Hi milkshakeii, what the topic today ?
[2:31 PM] Formula350: Hallo. Glad you're OK :P
[2:31 PM] milkshakeiii: i can talk about the technical side of foldit
[2:31 PM] ZeroLeak7: can we ask questions?
[2:31 PM] milkshakeiii: yes!
[2:31 PM] ZeroLeak7: ok
[2:32 PM] ZeroLeak7: could you tell us more about what you are currently working on, is it just bug fixing or new features? and the second question is, if I copy something from the foldit editor and paste it into notepad ++, the formatting is wrong and only a long line of text is displayed. Will there be a fix for this anytime soon?
[2:33 PM] Formula350: Q2: If you're running DevPrev, then Josh will have to look into that again, but as far as I know it HAS been fixed already.
[2:33 PM] robgee: ZeroLeak7 you can use edit-EOL conversion in notepadd++
[2:33 PM] milkshakeiii: we don't like to talk about stuff that's in the early stages because we don't know exactly what form it will take by the time it gets to the players
[2:33 PM] milkshakeiii: today is my first day back from holiday and I'm working on a performance issue that we're seeing since around the time of the QoL patch
[2:34 PM] milkshakeiii: the second question is something Josh has been working on
[2:34 PM] milkshakeiii: I assume it has to do with line endings so you could try changing the line ending character in notepad++
[2:34 PM] Formula350: Yea it's fine in DevPrev, however, there are additional line-breaks included, but that's not so bad.
[2:35 PM] ZeroLeak7: ok ty yes it has to do with the line ending
[2:36 PM] Formula350: Editor to Notepad copy-paste results in DevPrev.
[2:37 PM] ZeroLeak7: oh good it has been fixed in DevPrev.
[2:37 PM] Dudit: @milkshakeiii Is there any performance difference between 32 bit vs 64 bit Foldit?
[2:38 PM] milkshakeiii:
Dudit 32 bit applications can only utilize a limited amount of RAM
[2:38 PM] milkshakeiii: However I believe Foldit should always stay under the limit
[2:39 PM] milkshakeiii: In general I would say avoid 32 bit applications
[2:39 PM] milkshakeiii: But in theory the performance shouldn't be too different
[2:39 PM] Huubr: Is Foldit on Windows a 64 bit application?
[2:39 PM] Formula350: Avoid... IF you have the option. lol
[2:39 PM] ZeroLeak7: no
[2:39 PM] Formula350: Cuz... we no haz the option for Foldit :P 32bit only on Windows.
[2:40 PM] milkshakeiii: i didn't actually know we were still posting 32 bit versions yeah
[2:40 PM] Huubr: Mine is in C:\Program Files (x86)\Foldit
[2:40 PM] milkshakeiii: i don't think we are (edit: nevermind)(edited)
[2:40 PM] Formula350: I know Mac's are 64bit (I think Linux as well), but Windows is still 32bit
[2:40 PM] Formula350: "20201223-e20c1e0f15-win_x86-devprev"
[2:41 PM] milkshakeiii: jflat would be the one who would know that
[2:42 PM] Formula350: What's your personal greated accomplishment with Foldit this year?
[2:42 PM] Formula350: greatest* (I can words)
[2:43 PM] milkshakeiii: probably implementing the metrics although they haven't been as useful as we'd hoped, but there's more possibilities for using that functionality in the future
[2:43 PM] ZeroLeak7: what do you think, you can get more performance out of foldit?
[2:43 PM] Formula350: "haven't been", in terms of producing better science results?
[2:43 PM] milkshakeiii: yes I definitely think I can get a lot more performance out of foldit
[2:44 PM] Dudit: @milkshakeiii Is Windows Foldit 64 bit version under development?
[2:44 PM] milkshakeiii: there's a lot of subobtimal behavior
[2:44 PM] ZeroLeak7: yeah awesome
[2:44 PM] Formula350: (Cuz persoanlly, aside from the performance, I love the Metrics.)
[2:44 PM] milkshakeiii: it terms of the asynchronous nature of them paying dividends
[2:45 PM] Trigger:The metrics need to be weighted properly. In one puzzle they were worth thousands of points, in others, a hundred. How important are they, compared to energy?
[2:45 PM] milkshakeiii: I'll have to ask about windows 64 bit, it feels a bit silly to be still making 32 bit versions in 2021, but it's a project with a long legacy
[2:46 PM] milkshakeiii: we want people to be highly motivated to reach a certain threshold on the metrics
[2:46 PM] milkshakeiii: but we don't want them to spend a lot of time optizing the value after it passes a threshold
[2:46 PM] ZeroLeak7: yes would be nice if on all platforms is 64 bit
[2:46 PM] Huubr: Did both of you mean "more performance" in terms of speed, or better results for science? The ideal situation would be to have both, of course, but if given the choice, I would go for science, not speed.
[2:46 PM] Formula350: LOL That's the nicest way I've heard the code be referred to... "a long legacy"
[2:47 PM] milkshakeiii: i agree science is better than speed, but hopefully speed can lead to better science
[2:47 PM] milkshakeiii: as long as it has all the same functionality just better ha
[2:47 PM] ZeroLeak7: yes that's it
[2:48 PM] Formula350: Yes, if you can do more in the same time, you'll tackle more possibilities, which can yield better science. And indeed, if corners aren't being cut, just optimization of code.
[2:48 PM] Huubr: I will probably need to speed up my brain, then. :-)
[2:48 PM] milkshakeiii: haha
[2:49 PM] ZeroLeak7: yes you can implant a neuro chip from elon musk
[2:52 PM] robgee: Does the foldit codebase keep up with modern algorithms ?
[2:53 PM] milkshakeiii: yes our protein folding algorithms come from rosetta which is under constant development
[2:53 PM] ZeroLeak7: ah in which version is it written of c++ ?
[2:54 PM] Trigger:Are any of the AlphaFold algorithms public domain, and if so, when will we see them added to the functions we normally use?
[2:54 PM] milkshakeiii: c++11
[2:54 PM] ZeroLeak7: thats old
[2:54 PM] milkshakeiii: not as old as Foldit!
[2:54 PM] Formula350: Would it be possible to port the Metrics calculations to OpenCL, to let the GPU calculate those instead of the CPU? And as a followup to Rob's... there was mention that Foldit would be getting a Rosetta update that would be talked about, but I haven't seen anything... That still happening?
[2:55 PM] milkshakeiii: the alphafold algorithms aren't public domain yet but researchers have built their own neural nets and we are looking into ways to incorporate some of the nn algorithms into Foldit
[2:56 PM] milkshakeiii: GPU utilization also has some things stewing, but more on the scientist side, it's a bit of a long path before it makes its way to Foldit, but there is a path
[2:57 PM] milkshakeiii: Rosetta update is still happening, indeed
[2:58 PM] Formula350: I like the science side, too! I figured offloading metrics might be easier in the short term heh
[3:00 PM] ZeroLeak7: thats sounds good
[3:00 PM] Formula350: Do you happen to know what the benefits are to us end-users, with the Rosetta update, in terms of what would be readily obvious to us?
[3:01 PM] milkshakeiii: more possible objectives would be the main thing
[3:01 PM] milkshakeiii: all of the fundamental stuff should stay the same
[3:02 PM] milkshakeiii: I believe it's the exact same score function
[3:02 PM] Formula350: Basically it'll be adding more "science" that will be untapped.
[3:06 PM] pc: hi
[3:00 PM] Formula350: Do you happen to know what the benefits are to us end-users, with the Rosetta update, in terms of what would be readily obvious to us?
[3:01 PM] milkshakeiii: more possible objectives would be the main thing
[3:01 PM] milkshakeiii: all of the fundamental stuff should stay the same
[3:02 PM] milkshakeiii: I believe it's the exact same score function
[3:02 PM] Formula350: Basically it'll be adding more "science" that will be untapped.
[3:06 PM] pc: hi
[3:06 PM] pc: oh I forget the office hour ^^
[3:06 PM] ZeroLeak7: it is now
[3:06 PM] Formula350: Hallo. It's still going, if you have any non-science Q's for him
[3:10 PM] Formula350: My other "compute pitch' is wayyy out there in terms of actual usefulness... Maybe seeing if recipes could be ported to soimething like Shaders, to process. (I'm not even sure if it's possible though)
[3:12 PM] pc: when we want to move a protein by keeping left mouse button pressed, there is something like a velocity. I makes time before starting move, and often it is moved too far. Is there a way to move protein slowly with precision ? I know we can cut, and move with the arrows and join again. but the residue is not ideal after that.
[3:12 PM] milkshakeiii: you mean the pull tool, right pc?
[3:13 PM] milkshakeiii: yeah i don't love the way it works either
[3:13 PM] pc: yes pull tool
[3:13 PM] milkshakeiii: the reason is because it's doing optimization as it runs
[3:13 PM] pc: sometimes we need to move with more precisions. In linker puzzles for exemple
[3:14 PM] Formula350: It's not horrible in small puzzles, but once you add in the Objectives, it does become clunky. Even pulling on Sidechains to change their rotamer has the same issue :\
[3:14 PM] milkshakeiii: it's definitely part of what i'm looking at in terms of performance
[3:14 PM] Formula350: Does the Wiggle Power impact the Pull tool?
[3:14 PM] Formula350: I know CI does...
[3:14 PM] milkshakeiii: i'm not sure
[3:15 PM] Formula350: If so, PC you could try setitng it to Low and see if that helps...
[3:15 PM] pc: of course "enable cut band" off is better is some cases too
[3:15 PM] pc: when on, it can help, but the force is maybe too strong sometimes.
[3:16 PM] Formula350: It won't impact a pull if ther aren't any cuts.
[3:16 PM] ZeroLeak7: yes you should do it off
[3:16 PM] Formula350: If there IS a cut, then yes, turning it off will free it to move easily, as it won't be "banded" to the rest of the protein.
[3:18 PM] robgee: milkshakeii could you mention some of the optimisations you have in mind, would that be stuff like reducing array writes, flattening nested loops , memoization, etc ?
[3:18 PM] Huubr: Speaking about moving with more precision than with a mouse: I would love to be able to select a residue in the Rama Map, and then move it using the cursor keys, pixel by pixel.
[3:18 PM] milkshakeiii: eliminating redundancy is the first thing
[3:19 PM] pc: In linker puzzles, when I want to close the last cut point, I never know if it is in a good position. It is hard to see.
[3:19 PM] milkshakeiii: as in eliminating unnecessary iterations, then eliminating unnecessary operations within a single iteration
[3:20 PM] milkshakeiii: the stuff you mentioned might come into play, just basic "fix the time complexity" techniques
[3:20 PM] milkshakeiii: and after all that making things more asynchronous in a way that doesn't mess with game flow
[3:21 PM] milkshakeiii: or hopefully improves game flow
[3:21 PM] milkshakeiii: it's usually stupid stuff, as it so often is in software engineering
[3:22 PM] milkshakeiii: for example last patch I stopped a bunch of things like deleting rubber bands from causing the whole score function to be rerun (deleting a rubber band can't affect the score)
[3:22 PM] ZeroLeak7: too many cooks make the soup too salty
[3:23 PM] Formula350: Too many chefs cook way too much spaghetti :P
[3:24 PM] robgee: sweet, love that kinda thing. optimising away a chunk of code feels so good :)
[3:28 PM] ZeroLeak7: we have a great dev team now thank you for your time @milkshakeiii and have a good start in the New Year! and stay well!
[3:29 PM] milkshakeiii: thank you for your positivity ZeroLeak!
[3:29 PM] milkshakeiii: happy new year to you!
[3:29 PM] ZeroLeak7: yes always positive thank you
[3:29 PM] pc: Foldit is a good project. I hope we will find medications
[3:29 PM] milkshaeiii: and happy new year to all folders 8)
[3:29 PM] Formula350: Indeed. It's nice to see Foldit getting some much needed under-the-hood love finally!
[3:30 PM] Dudit: @milkshakeiii Thank you very much!
[3:30 PM] robgee: Thanks milkshakeii, Happy New Year to you and the foldit team.
[3:30 PM] Formula350: Happy near years to you as well. :)
[3:31 PM] pc: there where some good improvements in Foldit this year ^^

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hour 1/17/21: led by horowsah

[10:00 AM] horowsah:hi all- I’m here for an office hour! I’m usually involved in educational things and electron density puzzles, and on the rare occasion we try an RNA or DNA puzzle. I’m a biochemist, so I can also answer general biochemistry questions, but I’m not a true expert in protein design specifically, and definitely not the diseases that we’ve been having a lot of binder design puzzles for.
[10:00 AM] pc: hi horowsah
[10:02 AM] horowsah: i really should change my picture, come to think of it
[10:03 AM] pc: do you have some scientific feedbacks for linker puzzles ? We dont know what to try for now. We moslty make 5 helix and have good objectives score.
[10:03 AM] horowsah: so if i recall, we've mostly been asking for inflexible linkers, right?
[10:04 AM] pc: yes
[10:04 AM] horowsah: it's a tough challenge, because to be maximally effective, the linkers need to have good packing interactions
[10:04 AM] horowsah: on both sides, and ideally internally within the linker itself
[10:05 AM] spvincent: perhaps in that case we need more residues to work with
[10:05 AM] horowsah: how long have the linkers been so far?
[10:06 AM] spvincent: up to 250 but that includes the fixed bits.
[10:06 AM] horowsah: yeah, as you probably know, we try to keep puzzles under 250 because for a lot of people it slows down too much
[10:06 AM] horowsah: even with some parts fixed
[10:07 AM] horowsah: but there might be some things we could try to increase the size more
[10:07 AM] spvincent: theres something of an incompatibility between core filter values and interactions with the fixed elements
[10:08 AM] pc: In this 2 loops zone, maybe there is a problem to make the protein folding correctly. So sometimes I try to make bouds between the 2 loops. Is it correct, or we should avoid 2 loops beeing too close ?(edited)
[10:09 AM] SuperNova185:Different tech issue: I get site security alert on the portal url w EDGE browser (although the cert is valid) but not TOR or CHROME. can you explain why this is so?
[10:09 AM] horowsah: @spvincent i think you're right about a bit of an issue with the filters not being perfect for this sort of puzzle, it's something to improve on
[10:09 AM] horowsah: @pc: you see this sort of thing in nature, but usually it's very flexible and not all that stable. So it might not be the best strategy here.
[10:10 AM] horowsah: @SuperNova185 I really don't know, let me pass that one onto someone who might know that
[10:10 AM] pc: thanks
[10:10 AM] SuperNova185:Thanx
[10:11 AM] spvincent: when will we get some feedback as to which style of linker design looks most promising?
[10:12 AM] horowsah: i was just hearing that some are going to be experimentally tested in the near future, although don't quote me on that as i think i'm two steps removed from that actually happening.
[10:12 AM] spvincent: ok thats good.
[10:14 AM] pc: Here I made more bouds. Maybe it is better. If we resolve all buns in this loop zone, is it ok ?
[10:14 AM] susume: are there any plans for any ED puzzles soon?
[10:15 AM] SuperNova185:@susume: and DeNovo. I remember that you like those.
[10:15 AM] horowsah: @pc: getting rid of buns will help, but it still is usually better to try and get some regular secondary structure in there, like maybe to widen it out make make some sheets?
[10:15 AM] SuperNova185:@susume: DeNovo puzzles, that is.
[10:16 AM] horowsah: @susume: sadly, no ED puzzles in the very near future, but I think it would be good to do that soon
[10:17 AM] susume: I had this idea foldit players were going to have a chance to re-interpret some problematic structures from the PDB using our ED skills, but I wonder now if alphafold might do that better (though I also sense there is not much appetite for doing it at all)
[10:17 AM] horowsah: good question- there's a few parts to that
[10:18 AM] horowsah: it seems like alphafold is really good at getting the overall fold right, but the details of sidechains and such it doesn't always get right
[10:18 AM] horowsah: so that's a spot where humans are likely still going to be needed
[10:18 AM] pc: The same zone but in different view. One of the other solution to avoid this can be let a little hole. But maybe it is worse. So maybe I should try other configuration to avoid this zone.
[10:18 AM] horowsah: and i doubt they have any immediate plans to get it working well with ED
[10:19 AM] SuperNova185:What skillset is required to be a DevPrev reviewer?
[10:19 AM] horowsah:@pc: yeah i see the issue there, it would be good to close that somehow, but that one seems tough
[10:19 AM] horowsah: @SuperNova185 mostly the tolerance to handle a lot of crashes and not get frustrated! There's probably more to it than that, but I'm not actually sure
[10:21 AM] spvincent: Slightly off topic, but I was wondering what is the future of Rosetta in this time of AlphaFold?
[10:22 AM] horowsah: @spvincent i consider it on topic, since it's pretty related to the science of Foldit. Again, it's a complicated answer. First, it's likely Rosetta will incorporate the advances of AlphaFold2 into itself within a couple of years
[10:22 AM] horowsah: and that will make certain tasks in Rosetta considerably more powerful; it will probably improve protein design both within Rosetta and for Foldit, for example
[10:24 AM] horowsah: @SuperNova: in answer to your devprev question, anyone can play it who would like
[10:25 AM] susume: I believe a hybrid of Rosetta with trRosetta, plus a new quality assessor called DAN, was Baker lab's best prediction model in the last CASP - Dr Baker has recommended to his lab that they all use this model for structure prediction of designed proteins now, rather than Rosetta forward folding (which was the gold standard until now)
[10:25 AM] spvincent: Tx. I'm wondering how AlphaFold2 would manage if you gave it a protein with novel amino acids: it has nothing to train on in such a case
[10:25 AM] horowsah: @susume: that's what I've heard as well
[10:25 AM] horowsah: @spvincent unnatural amino acids are something it would probably fail at
[10:27 AM] spvincent: So you would still have to use Molelular Mechanics-based prediction in such a case.
[10:27 AM] horowsah: yep, good old fashioned physics
[10:28 AM] spvincent: Well good old fashioned physics should have cracked the problem. Yet progress seemed to stall a decade or so ago looking at the Casp results
[10:28 AM] spvincent: Whats the missing ingredient?
[10:28 AM] pc: Rosetta have values built from natural proteins. So, is there a difference in precision with the proteins we create in foldit?
[10:29 AM] horowsah: quantum mechanics, for one. Also, imperfect modelling of water is a big issue
[10:30 AM] horowsah: @pc: novel folds, such as those built by foldit players that don't exist in nature, presumably could cross out of areas in which Rosetta has it's best coverage from a fragment sampling perspective, but I think it's probably a pretty small inaccuracy in the grand scheme of things
[10:30 AM] spvincent: Any plans to add QM to Rosetta? Perhaps limited to interesting parts of the protein, such as the active site of an enzyme?
[10:31 AM] horowsah: that's a good question, and i wouldn't be surprised if someone is working on it, but i haven't heard about it
[10:31 AM] spvincent: tx
[10:31 AM] horowsah: in general, hybrid qm/ molecular mechanics force fields are still a work in process
[10:32 AM] spvincent: A trio of scientists won the Nobel prize for work in this area some years ago IIRC
[10:32 AM] susume: trRosetta doesn't know anything about physics, but it makes Rosetta much more effective by narrowing the space Rosetta has to search for (physics-based) energy minima - I expect alphafold 2 will have the same effect only much more so
[10:33 AM] horowsah: presumably it will, and the two will likely work together well
[10:34 AM] susume: there are people thinking about how to add trRosetta to foldit, and there are people at Baker lab planning to build the next generation of trRosetta based on alphfold2, so eventually that will hopefully also come to foldit
[10:34 AM] horowsah: ...but it might take awhile
[10:35 AM] spvincent: Have DeepMind actually published their results yet?
[10:36 AM] horowsah:
they published on alphafold1, but i would guess alphafold2 will probably not be published for a year yet
[10:36 AM] spvincent: I wonder if there'll be an AlphaFold3
[10:36 AM] horowsah: i hope so!
[10:36 AM] pc: When Mers puzzles lab tests will be done (and when we will have results ^^)
[10:37 AM] horowsah: i've heard some chatter about it, but they are apparently not easy, so i don't know the eta on those
[10:39 AM] susume: unrelated to foldit - is it true that imaging proteins with structural metal ions is difficult with x-ray crystallogrpahy, and do you know if cryo EM is making that easier?
[10:39 AM] horowsah: actually, i published a paper on that recently
[10:39 AM] pc: if mers puzzle worked, that means maybe the current metrics are goods ^^(edited)
[10:39 AM] susume: oo, link pls?
[10:40 AM] horowsah: https://journals.iucr.org/d/issues/2019/12/00/wa5123/
Acta Crystallographica Section D
Identifying dynamic, partially occupied residues using anomalous sc...
Structural studies of partially occupied, heterogeneous protein systems using crystallography are difficult. Here, methods are presented for detecting these states in crystals.
[10:40 AM] pc: nice
[10:40 AM] horowsah: crystallography is actually really good at identifying metals... if you have the right beamline
[10:40 AM] horowsah: cryo-em probably won't be as good at it for a long time
[10:41 AM] horowsah: @pc: we can hope, but the metrics are likely going to be improving still in the future
[10:42 AM] susume: ty, will definitely read! I'm taking a class on metals in biomolecules
[10:42 AM] horowsah: back to the question of imperfections in our ability to computationally model proteins: metals are near the top of the list
[10:43 AM] horowsah: there's a reason you don't see too many of them in foldit puzzles
[10:45 AM] spvincent: What are the issues?
[10:46 AM] horowsah: ok, take this with a grain of salt since i'm not an inorganic chemist, but metals have a way of binding things that are somewhat in between what we think of as covalent bonds and weak bonds that you manipulate in foldit, for example
[10:46 AM] horowsah: and classical physics has a tough time handling it for some reason that i'm not entirely sure of
[10:47 AM] horowsah: so usually metals are handled in a way that is pretty ishy
[10:47 AM] horowsah: and even our quantum mechanics models don't do a great job with a lot of metals
[10:48 AM] horowsah: @susume: that paper only makes brief mention of metals, but the concept is the same as to what we were looking at; metals have distinct edges for anomalous scattering that can be picked up by x-ray crystallography and not that many other techniques
[10:51 AM] spvincent: It used to be the case that there was a bit of question mark hanging over structures obtained with X-ray crystallography: was the crystal structure the same as the one in solution.
[10:51 AM] spvincent: Does this still persist?
[10:51 AM] horowsah: people like to dredge up that argument from time to time but it really only applies in rare cases
[10:52 AM] horowsah: but if you want to see a fun one:
[10:52 AM] horowsah: https://www.pnas.org/content/99/5/2806
Crystal structure of an antiparallel DNA fragment with Hoogsteen ba...
We report here an alternative double-helical structure of the DNA molecule. It has been found in the d(ATABrUAT) and d(ATATAT) sequences by single-crystal x-ray crystallography. This sequence is found not only in TATA boxes, but also in other regulatory regions of DNA. Bases of the two antiparallel strands form Hoogsteen pairs, with adenines in ...
[10:52 AM] horowsah: for the most part, crystallography really does show what happens in solution
[10:53 AM] horowsah: that paper is an entire dna helix in which hoogsteen base pairing happens instead of watson crick base pairing
[10:53 AM] horowsah: and while hoogsteen pairing is thought to occur rarely (like 1% of the time or less), an entire helix doing it simultaneously is probably an artifact of crystallography
[10:54 AM] spvincent: tx I'll look at it later. gtg: thanks for answering questions horowsah.
[10:54 AM] horowsah: np
[10:57 AM] susume: since @Formula350 is not here I will ask his signature question - is there anything you as a scientist wish that foldit players would do more of, or anything you wish we would do less of?
[10:58 AM] pc: In Foldit, is it better to play for points, and try to find the metrics limits, or to think about science, and make more viable solution but with less points ?
[10:59 AM] horowsah: so my answer to both of those questions is: it's best to try for novel solutions that are outside the box. Sometimes this makes it tougher to get the high score, but it's more scientifically valuable to be unique in your approach and solutions
[10:59 AM] pc: thanks
[11:00 AM] horowsah: thanks all, i have to run!

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hour 2/5/21- led by Sciren

[3:07 PM] scriren: How is everyone doing today?
[3:09 PM] HuubR:I'm fine, thanks. A bit surprised about the office hour; I did not see the announcement, but that is actually a pleasant surprise.
[3:09 PM] HuubR:What will be the general subject?
[3:13 PM] scriren:
Hi HuubR so a little bit about myself. I am a software developer working on Foldit with the Meiler Lab in Nashville TN. I primarily work on Small Molecule design. I know there haven't been any small molecule puzzles lately, but we have a few things in the works and are hoping to get them out sooner rather than later
[3:14 PM] HuubR:Small molecule, as in Ligand Design? The only one I remember was 1955 (July last year), but then again I have only been folding since April :-)
[3:15 PM] Susume: cool! I can't remember, are the small molecules all organic, or are there other groups/ions available?
[3:15 PM] scriren: Yes indeed Ligand Design
[3:15 PM] spvincent: What kind of things Sciren? There have been some occasional logand design puzzles in the past but they've always been a bit buggy.
[3:16 PM] Susume: you are working on the pick-from-column-A, pick-from-column-B interface, right?
[3:17 PM] scriren: To your first question Susume we are focusing mostly on organic ligands.
[3:18 PM] scriren: Yes so I have been working on the Reaction Design Tool. This is the tool where you have the choice of partial structures to choose from to create your ligand.
[3:18 PM] HuubR:I think it would be great when we can work on parts of a ligand just as we do on individual residues (Selection Interface). What I remember from Puzzle 1955, the ligand was one big segment, although we composed it of three reagents.
[3:19 PM] scriren: The purpose of this is to help players create synthetically viable compounds that can be created in the lab.
[3:20 PM] scriren: How so HuubR? I'm not sure I followed.(edited)
[3:22 PM] scriren: Oh and to your question @spvincent I'm working to update Reaction Design Tool to help fix some of the known bugs as well as updates to the tutorial.
[3:23 PM] spvincent: tx
[3:24 PM] HuubR: Well, forgive me for being direct, but I think a lot of players did not like the three column user interface. My idea would be that a ligand is composed of three segments, and you can replace one (or more) of these segments by other reagents, just as you can mutate single residues. Q1: Does that make sense? Q2: is it possible to do that in the program?
[3:24 PM] scriren: I'm also working on an updated version of the Ligand Design Tool that takes a more atomistic approach. Where you can create your ligand (or modify it) by changing the atoms and bonds.
[3:25 PM] HuubR:That sounds even better than my suggestion :-)
[3:26 PM] Josh: you should see the mock-ups HuubR. I've seen them and Sciren is doing some amazing UI work
[3:26 PM] spvincent: Hasn't there been a lot of computational chemistry done over the years on this? Can Foldit players really improve on massive computational efforts such as OpenPandemic at the WCG?
[3:26 PM] Josh: he's taking Foldit in a beautiful direction
[3:27 PM] scriren: That's great to hear! No worries about the directness. I want to know how players use the tools provided and how to make them better!
[3:28 PM] scriren: Awe thank you very much @Josh Its also great that you mention this because I want to share with the everyone the design for the new builder.
[3:28 PM] Skippysk8sIRC: I felt like a kid with a chem set in grade school I had no idea what order the selected pieces would assemble, so it felt random to me. My lack of organic chem probably doesn't help
[3:30 PM] scriren: I wanted to share this with you all, but I need to make clarify that this tool is under much revision and this will almost certainly not be the final iteration.
[3:30 PM] scriren: but this is the direction that I am trying to take the Ligand Design Builder
[3:32 PM] HuubR:Cool! It looks like a remote control. Where is the "detonate" button? :P
[3:32 PM] Skippysk8s: I can detonate anything .o.
[3:33 PM] HuubR:lol
[3:33 PM] scriren: @spvincent I think that Foldit players do have a lot to contribute especially when you take the spacial recognition abilities players excel at and couple them with the ligand-protein interface.
[3:33 PM] scriren: Haha! I haven't added that one yet, but like I said this is subject to change so there is always time to add it in
[3:35 PM] spvincent: It will be nice to have some variety in the puzzle types. Look forward to trying it: any idea when we'll get the first one?
[3:35 PM] scriren: My hope is, once the design is in a more solidified state, to open a sandbox style ligand puzzle as well
[3:37 PM] HuubR:Can you give any indication about the time frame for that?
[3:38 PM] scriren: What I can say is that I am working on getting this into your hands as soon as possible. I know that that isn't always the most satisfying of answers, but I want to make certain that you all have the best experience possible.
[3:40 PM] HuubR:It's probably not the answer we hoped for, but it's an honest answer, and therefore a good one.
[3:42 PM] scriren: Thank you. I very much want to see all the awesome science that can be done with these tools in your hands, so as a developer I am very excited to get this to you when it is ready.
[3:42 PM] Susume: I really like the interface - sleek, easy to understand (much better than the actual chemistry!)
[3:43 PM] scriren: I'm a gamer as well so I also understand what the anticipation is like.
[3:44 PM] HuubR:Just a first remark after admiring these beautiful pictures: on SideOne, I would expect N, O, and F in that order (7, 8, 9). Is there a specific reason to put O first?
[3:44 PM] scriren: Thank you @Susume the hope with this type of interface to get players up and running as intuitively as possible.
[3:45 PM] Skippysk8s: I think some of my problem with the last puzzle was an inability to control the orientation of the ligand . I'd end up with the wrong end trying to connect
[3:46 PM] Susume: F, Cl, I and Br (the halides) all act similarly in a molecule, so they can be swapped out, makes sense to me they are in a box together
[3:46 PM] HuubR: Yep, agree
[3:46 PM] pc: oh there is a office hour
[3:46 PM] pc: hi
[3:47 PM] scriren: HuubR I put O on the left hand side because I found myself using it more often and it was an ease of use decision.
[3:47 PM] scriren: You are correct @Susume !
[3:47 PM] scriren: Yes indeed! Hello @pc !
[3:47 PM] Susume: oh I see what you mean, yeah maybe N should go above P (they both like 3 bonds) and O above S (they like 2 bonds)
[3:48 PM] HuubR:Like in the periodic table.
[3:48 PM] scriren: That's actually a really good point and one that I can look into!
[3:49 PM] spvincent: There was a previous incarnation of the small ligand design tool that looked something like this. I had problems using it: I was never sure what it was that I was creating.
[3:49 PM] scriren: One of the original concepts that I worked on was arranged more like the periodic table, but to do the groups as @Susume mentioned, it was a little troubling to look at for anyone when a chemistry background.
[3:50 PM] Susume: when we get the heavy atoms wher we want them, can we fill all empty spots with H with one click?
[3:50 PM] pc: I imagine new molecule puzzle, with contextual menu to gradualy add atoms, keeping bouds in current molecule in game.(edited)
[3:50 PM] scriren: That is a use case that I haven't checkout out, but I can look into it.
[3:51 PM] Dudit: @Sciren I think the Objectives (Filters) UI/UX in Foldit needs to be improved (like the Formula350 suggested)
[3:53 PM] scriren: I think I see what you are saying pc. You are talking about just creating a molecule by growing it piece by piece?
[3:53 PM] pc: yes, like in design puzzles when we add residues
[3:54 PM] scriren: @Dudit I agree and I can assure you that it is being worked on as well.
[3:54 PM] spvincent: It might be too easy to create implausible molecules by just successively adding atoms.
[3:55 PM] scriren: Indeed, this is one of the issues with this approach.
[3:56 PM] HuubR:Would it be feasible to come up with a scoring system that tells you how plausible a certain molecule is?
[3:56 PM] pc: I imagine that there is constrains, so a contextual menu can show what we can add each time or not
[3:56 PM] scriren: Work is being done as well to help guide players to creating synthetically viable molecules. It isn't easily done, but we are working on it.
[3:57 PM] scriren: It's the entire premise behind the Reaction Design Tool, and one of the reasons I am working to improve it.
[3:58 PM] HuubR:Sounds like quite a challenge. The possibilities are, well, almost endless.
[3:59 PM] pc: In last puzzle I tested, each time I wanted to modify my molecule, I losed the position, rotation, and all bonds I have succesdeed to do.
[3:59 PM] scriren: Is this the Reaction Design Puzzle?
[3:59 PM] pc: yes
[4:00 PM] HuubR:@pc, I agree. It was not possible to leave the ligand in place and modify just one end of it. At least, I did not manage to do that.
[4:00 PM] jeff101: it would help to have LUA tools to list atom types for each atom in the ligand (C, N, O, Cl, etc) and perhaps even different types of C, N, and O atoms based on how many other atoms they bind to
[4:00 PM] scriren: Yes positional alignment is one of the issues being worked on.
[4:01 PM] scriren: That is something I can look into jeff101
[4:01 PM] scriren: Sort of a labeling system outside of the color scheme?
[4:02 PM] jeff101: like carbons can be part of CH3 or C=O
[4:02 PM] jeff101: O can be part of C=O or -OH
[4:03 PM] jeff101: carbons can be part of rings
[4:03 PM] pc: There were this menu. And the current molecules used in game where not selected when we open this menu. So we couldnt know what other molecule to choose, because we didnt know what where the current.
[4:04 PM] scriren: Oh I see, you mean something like listing functional groups. I can look into see if there is a good way to list common groups to help players build.
[4:05 PM] HuubR: @pc, scroll back to 23:31h (CET). The new user interface is awesome!
[4:05 PM] scriren: Ah yes, there should be an update soon @pc fixing the selection issue. A little "behind the scenes" info on that bug. When the tool is first loaded a selection was being made that was not being highlighted. I was able to track it down and correct it.
[4:05 PM] pc: cool
[4:06 PM] BootsMcGraw:It was very difficult for me to see which choices were selected when using the tool.
[4:07 PM] pc: the idea is that we cant to test multiple configurations like when we change some amino acids one by one to make some bouds (but I know we can use "mutate" too ^^)
[4:08 PM] BootsMcGraw:IMAGE: http://fold.it/portal/files/chatimg/irc_82314_1612566502.png

[4:08 PM] BootsMcGraw:IMAGE: http://fold.it/portal/files/chatimg/irc_82314_1612566519.png

[4:08 PM] scriren: I see what you are saying BootsMcGraw, the highlight isn't dynamic enough. I can place that within a future update. I'm working on getting a labeling system to you as well and I think that should shore up some confusion.
[4:08 PM] BootsMcGraw:IMAGE: http://fold.it/portal/files/chatimg/irc_82314_1612566527.png
[4:08 PM] pc: and maybe a "mutate" tool can by possible too to chose and add the best molecule extension at a current point
[4:08 PM] jeff101: I wrote at least one feedback about the last version of the REaction Design Tool. Some changes were less radical than the ones you are proposing in this office hour. One example is to keep the columns of reactacts but number them within the tool so it is easier to tell your teammates which reactant you chose for each column
[4:09 PM] jeff101: also to have LUA commands that would list which reactants were chosen from each column
[4:09 PM] BootsMcGraw:Thank you, Sciren, on behalf of the colorblind contigent.
[4:09 PM] scriren: Yes indeed jeff101 that is one that I am working on currently, and will have it out as soon as possible.
[4:10 PM] scriren: Happy to help BootsMcGraw!
[4:12 PM] scriren: With that I am going to have to step out folks. Thank you so so much for all of your time and wonderful feedback. You all make this community amazing! I very much look forward to speaking with you all in the future! Happy Folding Everyone!
[4:13 PM] jeff101: when you tab on a designed ligand, it could list the formula for it like C6H5Cl
[4:13 PM] Skippysk8s: thanks
[4:13 PM] HuubR:Thanks, @Sciren!
[4:13 PM] Dudit: Thank you @Sciren

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hours 2/27/21- led by bkoep

[11:01 AM] bkoep: Hi @here! Welcome to office hours
[11:01 AM] bkoep: I'm bkoep, a scientist on the Foldit team
[11:01 AM] bletchleyPark:Hi bkoep
[11:01 AM] Dudit: Hello @bkoep
[11:01 AM] pc: hi
[11:01 AM] spvincent:hi
[11:01 AM] alcor29: Good morning.
[11:01 AM] bkoep: Here to talk about all things Foldit, and especially protein design
[11:02 AM] pc: @bkoep: When you study the solutions shared by the players, are repeated errors that you see a problem ? Or are you looking for a solution to give them feedback if needed (in a practical way of course, like a global feedback ? ).(edited)
[11:03 AM] Dudit: @bkoep Will there in the future a Foldit Designable Linker puzzle that is linking three or more proteins?
[11:03 AM] bletchleyPark:@bkoep: given the pandemic, I would welcome all focus on improving effectiveness of vaccines.
[11:04 AM] alcor29: How is the therapeutic LCB1 doing in trials?
@bkoep: When you study the solutions shared by the players, are repeated errors that you see a problem ? Or are you looking for a solution to give them feedback if needed (in a practical way of course, like a global feedback ? ).(edited)
[11:05 AM] bkoep: I do try to keep an eye out for common or repeated problems, because these seem to indicate problems with the way we are framing a challenge, or problems with the way we are scoring solutions
[11:06 AM] bkoep: One example of this is would be "triangular" H-bond networks in symmetric trimer designs, where three SER (or THR, TYR) form a tight equilateral triangle around the symmetric axis
[11:07 AM] pc: Thanks. the idea is therefore to make Foldit more intuitive.
[11:07 AM] bkoep: This was really popular among a lot of player designs, and we were able to adjust the H-bond scoring to discourage this
@pc Thanks. the idea is therefore to make Foldit more intuitive.
[11:08 AM] bkoep: Yes, exactly. One of the primary goals for the Foldit scientists is to make protein science as approachable as possible.
@bkoep: Will there in the future a Foldit Designable Linker puzzle that is linking three or more proteins?
[11:09 AM] bkoep: It's possible we could run a linker puzzle to connect 3+ domains, but unlikely.
[11:10 AM] bkoep: The main concern is puzzle size. The more residues that need to be modeled (and rendered) in a Foldit puzzle, the more demanding the puzzle will be for computational resources. A puzzle with three domains and two linkers might be pretty slow on a regular desktop.
[11:11 AM] bkoep: Also, that's a problem that I think we can easily split up into sub-problems
[11:12 AM] bkoep: If we get a bunch of solutions linking domain A -> B and in another puzzle we get solutions linking B -> C, then we can probably combine those solutions into A -> B -> C very straightforwardly. No need to model the final product in a Foldit puzzle
[11:13 AM] pc: @bkoep: Are current linker solutions good ? Some solutions had almost or all the objectives, what is missing to improve further?
bletchleyPark: @bkoep: given the pandemic, I would welcome all focus on improving effectiveness of vaccines.
[11:14 AM] bkoep: Yes! There is a lot going on in vaccine development research right now
[11:14 AM] bkoep: However, there aren't a lot of obvious ways that Foldit can be applied to the problem
[11:15 AM] bkoep: Vaccine effectiveness usually boils down to: finding out the best way to display an antigen to the immune system
[11:16 AM] bkoep: Most of that work involves working with known, well-characterized proteins (the antigens). There's not much of a role for protein structure prediction or protein design
[11:17 AM] bkoep: But there are still some opportunities to help indirectly
[11:17 AM] bletchleyPark: In what way do our binders fit in then ?
[11:18 AM] bkoep: For example, we might be able to use protein design to help modulate the immune response in the presence of a vaccine. A couple years ago we attempted to design binders for CR2; it's thought that controlling the activity of this cell surface receptor could improve immunological response to a vaccine
bletchleyPark: In what way do our binders fit in then ?
[11:19 AM] bkoep: Most of our binder design projects are attempts to develop a therapeutic
[11:20 AM] bkoep: This kind of therapeutic would be more like a drug that you could administer, to directly mediate the effects of a disease. In contrast, a vaccine is a strictly prophylactic formula that trains the immune system to handle future infections on its own
[11:21 AM] bletchleyPark:Sounds like a great way to contribute, are we on the right track with our therapeutic designs ?
bletchleyPark: Sounds like a great way to contribute, are we on the right track with our therapeutic designs ?
[11:23 AM] bkoep: Yes, I think so. Protein binder design is a very difficult problem, and we have only just started to tackle it in Foldit so we don't have much data yet
[11:23 AM] bkoep: But our computational analysis of Foldit player-designed binders suggests that the designs are up to snuff
[11:24 AM] pc: I suppose if Mers puzzle results are good, that would be decisive for this kind of puzzle ?
[11:24 AM] bkoep: What's left is to try and boost throughput (more designs) and to get experimental data from the lab
alcor29: How is the therapeutic LCB1 doing in trials?
[11:25 AM] bkoep: I'm sorry I don't have any inside info on the LCB in vivo testing. The last I heard, it was going into ferrets and probably soon into non-human primates
[11:26 AM] alcor29: Thanks bkoep:
@bkoep: Are current linker solutions good ? Some solutions had almost or all the objectives, what is missing to improve further?
[11:26 AM] bkoep: Yes! I think the latest linker design results have looked really good! I'm hopeful that we'll be able to get some experimental data soon.
[11:26 AM] jeff101:I'm doing trimer puzzle 1960 and wish I could add or remove segments. Is that possible in trimer puzzles?
[11:27 AM] bkoep: We are still figuring out the best way to set up puzzles for the linker design puzzles, so that the best scoring designs have a core that spans the entire protein, and good packing throughout
[11:27 AM] alcor29: Yes I would like to delete some segs also.
[11:28 AM] alcor29: On the trimer.
jeff101:I'm doing trimer puzzle 1960 and wish I could add or remove segments. Is that possible in trimer puzzles?
[11:28 AM] bkoep: Haha yes, this has been on our wishlist for a long time, and you might expect it would be a trivial feature to add
[11:28 AM] spvincent:Thats a long-standing issue that is apparently not easy to fix. Much as we would like it to be.
[11:29 AM] bkoep: Basically, the symmetry features in Foldit prohibit us from inserting/deleting residues as easily as we do in non-symmetric puzzles
[11:29 AM] HuubR: I really like to play Symmetry puzzles, but I have wondered what their scientific value is. Can you tell us something about that?
[11:30 AM] bkoep: There are other roundabout ways to implement the feature, but it will take some work and right now we are occupied with other development priorities
[11:30 AM] Dudit: @bkoep: Are there any plans to develop Windows Foldit 64bit ?
[11:30 AM] donuts554: hello
[11:30 AM] pc: @bkoep: Some linker solutions have 0 buns, all ideal loops, and a good core. What do you think we should focus on next ?
HuubR: I really like to play Symmetry puzzles, but I have wondered what their scientific value is. Can you tell us something about that?
[11:31 AM] bkoep: Of course! For me there are two primary motivations for symmetry puzzles
[11:31 AM] pc: I think straight helix is important too maybe
[11:32 AM] bkoep: The first motivation is that well-behaved symmetric proteins are extremely useful components for downstream applications
[11:32 AM] bkoep: Any kind of macro-scale protein materials (think synthetic silk, or membranes, or MOF-like bulk materials) will probably be built from symmetric components
[11:33 AM] HuubR: Can you define "well behaved"?
[11:33 AM] bkoep: So, the more well-behaved symmetric assemblies we have, the more easily it is for scientists to tackle those later projects
[11:33 AM] pc: interesting ^^
HuubR: Can you define "well behaved"?
[11:34 AM] bkoep: Yes, by "well-behaved" I mean things like: the protein is soluble at high concentrations; it self-assembles into the intended symmetry but not into off-target assemblies; it has a high melting temperature
[11:34 AM] bletchleyPark: @bkoep: I occasionally will run an optimization on an expired puzzle and post to scientists. Are you checking these 'late ' results ?
[11:35 AM] bkoep: The second motivation for symmetric design is that it can help us learn about designing protein-protein interfaces
[11:36 AM] HuubR: Maybe this will be another challenge for your programmers that is not a top priority, but would it be possible to make a Tetramer puzzle with two of the four subunits upside down? I see that in Wikipedia, in the 2nd picture for Tetrameric protein
[11:36 AM] HuubR: https://en.wikipedia.org/wiki/Tetrameric_protein
Tetrameric protein
A tetrameric protein is a protein with a quaternary structure of four subunits (tetrameric). Homotetramers have four identical subunits (such as glutathione S-transferase), and heterotetramers are complexes of different subunits. A tetramer can be assembled as dimer of dimers with two homodimer subunits (such as sorbitol dehydrogenase), or two h...
[11:36 AM] bkoep: The ultimate challenge is to be able to design a protein that can bind to an arbitrary target surface (this is "binder design"). In theory, it should be easier to design two proteins that bind to one another (or a protein that binds to itself), because we have control over both sides of the interface
[11:37 AM] bkoep: So we can focus on the low-hanging fruit (symmetric design) and still gain knowledge that will be useful for more difficult problems in the future (binder design)
[11:38 AM] HuubR: Thanks, that makes it a lot clearer!
@bkoep: Are there any plans to develop Windows Foldit 64bit ?
[11:38 AM] bkoep: I'm sorry, I'm not sure about plans to develop for 64-bit Windows. Are you unable to run the 32-bit app?
[11:39 AM] bletchleyPark:64-bit versions may handle the memory limitations better
[11:39 AM] alcor29: Is there ever a way for us to get to know something of what knowledge you are gaining when you look at our symmetric designs?
[11:39 AM] donuts554: Why is sulfur a nonpolar atom?
@bkoep: Some linker solutions have 0 buns, all ideal loops, and a good core. What do you think we should focus on next ?
[11:41 AM] bkoep: I think those are the biggest challenges for the linker solutions. We just need to make sure that a "good core" according to the Core Existence Objective is the same as a "good core" according to the protein engineers. These seem to be in agreement in the most recent puzzles, but it is still sometimes possible to satisfy the Objective and still have problematic "hinge" regions in the protein that allow movement of the linked domains
bletchleyPark: @bkoep: I occasionally will run an optimization on an expired puzzle and post to scientists. Are you checking these 'late ' results ?
[11:42 AM] bkoep: No, we do not look at puzzle solutions that come in after a puzzle expires
[11:43 AM] bletchleyPark:That is a pity
[11:43 AM] bletchleyPark:and good to know
[11:43 AM] jeff101:are there plans to change the ideal loops filter so a 3-residue non-ideal loop gives less penalty than a 12-residue one?
[11:43 AM] pc: thanks. And if we "share to scientist" some minutes after puzzle expire, it is not too late ?
HuubR: Maybe this will be another challenge for your programmers that is not a top priority, but would it be possible to make a Tetramer puzzle with two of the four subunits upside down? I see that in Wikipedia, in the 2nd picture for Tetrameric protein
[11:43 AM] bkoep: Yes, absolutely! In addition to cyclic tetramers (C4 symmetry), we can design dihedral tetramers (D2 symmetry) in Foldit
[11:44 AM] HuubR: :-)
[11:44 AM] jeff101:how about tetragonal tetramers (like 4-side dice in Dungeons & Dragons) ?
[11:44 AM] bkoep: I suspect D2 assemblies will be slightly more difficult to design, but it is certainly something we can try
[11:45 AM] pc: Solutions in design puzzles have more points for proteins with max residue count. Do you think the "residue count Objective" should be adapted ?
Is there ever a way for us to get to know something of what knowledge you are gaining when you look at our symmetric designs?
[11:47 AM] bkoep: Most of the "gaining knowledge" happens very late in a project, after we've met some success and we can step back and look at all of our experiments together
[11:48 AM] bkoep: (Sometimes we do not realize a conclusion until after we sit down and start to write a paper about our experiments)
[11:49 AM] alcor29: k
donuts554: Why is sulfur a nonpolar atom?
[11:51 AM] bkoep: Sulfur is on the edge of polar vs. non-polar (chemical polarity is more of a spectrum than a hard classification). Sulfur is slightly polar and can make weak hydrogen bonds, but it can also be buried without too much penalty
jeff101:are there plans to change the ideal loops filter so a 3-residue non-ideal loop gives less penalty than a 12-residue one?
[11:51 AM] bkoep: Probably not. In my eyes, a 3-residue non-ideal loop and a 12-residue non-ideal loop are equally problematic.
11:53 AM] jeff101:but for recipes, if the 3-residue ones have less penalty, it helps the recipe gradually reduce the # of residues involved in non-ideal loops
@pc thanks. And if we "share to scientist" some minutes after puzzle expire, it is not too late ?
[11:53 AM] bkoep: Please share your solutions before a puzzle ends. If you share a solution after the puzzle expires, we will probably not see it.
[11:53 AM] donuts554: How strong are the hydrogen bonds involving sulfur compared to pi stacking?
[11:54 AM] jeff101:now if a recipe fixes the middle of a 12-residue bad loop, it could end with two 3-residue bad loops, which gives a larger penalty
[11:53 AM] jeff101:but for recipes, if the 3-residue ones have less penalty, it helps the recipe gradually reduce the # of residues involved in non-ideal loops
@pc thanks. And if we "share to scientist" some minutes after puzzle expire, it is not too late ?
[11:53 AM] bkoep: Please share your solutions before a puzzle ends. If you share a solution after the puzzle expires, we will probably not see it.
[11:53 AM] donuts554: How strong are the hydrogen bonds involving sulfur compared to pi stacking?
[11:54 AM] jeff101:now if a recipe fixes the middle of a 12-residue bad loop, it could end with two 3-residue bad loops, which gives a larger penalty
[11:54 AM] Susume: jeff makes a good point, sometimes the importance of the score is that it provides something for recipes to optimize on, not just that it uniformly discourages undesired attributes
[11:55 AM] jeff101:if you have the penalty depend on the # of residues in non-ideal loops, recipes can gradually fix them
[11:55 AM] bletchleyPark:I'm off and will read up in the log, thank you for answering questions in this office hours bkoep:
[11:55 AM] bletchleyPark: afk
jeff101: how about tetragonal tetramers (like 4-side dice in Dungeons & Dragons) ?
[11:55 AM] bkoep: Yes, tetrahedral symmetry is also possible, but each "side" of the tetrahedron must have perfect C3 cyclic symmetry. So, in practice, you need at least 12 protein chains to make a tetrahedron. That's getting rather large for Foldit, so I would not expect a tetrahedral design puzzle anytime soon
@pc Solutions in design puzzles have more points for proteins with max residue count. Do you think the "residue count Objective" should be adapted ?
[11:56 AM] bkoep: Yes, we may need to recalibrate the score penalty for residue insertions
donuts554: How strong are the hydrogen bonds involving sulfur compared to pi stacking?
[11:58 AM] bkoep: I'm sorry I don't know this off the top of my head
[11:58 AM] jeff101:if we could read with LUA which residues are parts of non-ideal loops, our recipes might be able to fix such loops better
[11:59 AM] alcor29: Keeping inmind that fixing loops has, I think, become a real bugaboo for many folders.
[12:00 PM] jeff101:a recipe could count the # of continous residues in a non-ideal loop and then rebuild/remix the entire loop at once
[12:03 PM] pc: Rosetta score is good for the folding prediction, but in design puzzles, maybe it works less well for compare proteins which do not have the same number of residue. And in Design puzzles, virus and Binder are calculated by Rosetta score as if they were the same protein. Will the Objective always be enough to adjust score, or do you think you have an adapted new Rosetta score system ?
jeff101:if we could read with LUA which residues are parts of non-ideal loops, our recipes might be able to fix such loops better
[12:03 PM] bkoep: I think this is probably the ideal solution. We want the score function to reflect our scientific goals as accurately as possible. I don't like the idea of adjusting the score function to make a method more convenient; rather, I think the method should be adjusted in response to the score function
[12:05 PM] jeff101:I heard that some Foldit players are helping Josh code changes to Foldit (not just recipe writing, but writing new LUA functions, for example). Is this true?
@alcor29 Keeping inmind that fixing loops has, I think, become a real bugaboo for many folders.
[12:07 PM] bkoep: In a sense, this is a little reassuring. Loop closure is a huge problem everywhere in de novo protein design. It is a truly difficult challenge, so we should expect some difficulty in Foldit. Of course we would like to make it easier, but if Foldit players had no difficulty whatsoever with loop closure then I might become suspicious that we are modeling something incorrectly
[12:09 PM] jeff101: please make a LUA command that lists whether a segment is part of a non-ideal loop. then we can do trickier things in recipes to fix bad loops.
[12:09 PM] pc: it is very hard to join the last cutted point in linker puzzles yes
[12:10 PM] alcor29: Agreed if you are willing to give up quite a few designs. I try every possible approach to solving them and after all is done , I just accept the bad loops and give up. I gather though that quite a few others are having the same reactions.
[12:10 PM] alcor29: For my part I'm ok with it since I can only do what I can do.
@pc Rosetta score is good for the folding prediction, but in design puzzles, maybe it works less well for compare proteins which do not have the same number of residue. And in Design puzzles, virus and Binder are calculated by Rosetta score as if they were the same protein. Will the Objective always be enough to adjust score, or do you think you have an adapted new Rosetta score system ?
[12:11 PM] bkoep: The Rosetta score is supposed to reflect the energy of the system, so it is appropriate that two chains (e.g. binder and target) both contribute to the same score. But you are right that there are fundamental problems with the idea of optimizing score (energy) in a design puzzle
[12:11 PM] bkoep: (More about that in this blog post: https://fold.it/portal/node/2005623)
[12:11 PM] pc: thanks
[12:12 PM] bkoep: Actually, if we can manage it, we usually prefer to adjust the Rosetta score (instead of adding Objectives)
[12:12 PM] bkoep: We can model things more efficiently if everything is part of the Rosetta score function
[12:13 PM] alcor29: To rephrase I get that x number of designs will not be usefull. It just depends on how many casualties you are happy to accept.
[12:13 PM] bkoep: But we need for all terms of the Rosetta score function have to be differentiable and pairwise decomposable, and sometimes this is not possible for certain features
[12:14 PM] pc: the Rosetta score system in foldit, add sub-scores. But maybe there is synergy between some sub-scores, and it is better to multiply some and not just add ?
[12:15 PM] pc: and there is pairwise ok
[12:16 PM] HuubR: Thanks, bkoep:, for a very interesting Office Hour! Unfortunately, I have to go now.
[12:16 PM] HuubR: Looking forward to playing a D2 Tetramer puzzle :-)
jeff101:I heard that some Foldit players are helping Josh code changes to Foldit (not just recipe writing, but writing new LUA functions, for example). Is this true?
[12:17 PM] bkoep: Yes! We can share (most of) the Foldit source code to anyone who licenses Rosetta for non-commercial use (this is free to do). Contributing to the code is not easy, and since Foldit is not open-source we don't expect many people will want to contribute. But if you are interested, you should email mail.fold.it@gmail.com or send a PM to @Josh
[12:20 PM] jeff101:thanks bkoep:
[12:20 PM] jeff101:soon will be the monthly video about Foldit
[12:20 PM] pc: is it finish ?
[12:20 PM] pc: so thanks ^^
[12:21 PM] bkoep: Okay everyone I have to split
[12:21 PM] bkoep: Thanks all for the excellent discussion!
[12:21 PM] jeff101:thanks for having this chat
[12:21 PM] alcor29: Tx bkoep:
[12:21 PM] Dudit: @bkoep: Thank you very much!
[12:21 PM] pc: Thanks for answers. always usefull for us.
[12:21 PM] pc: and for Foldit team I hope too.

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hour 3/11/21- led by Beta_Helix

[9:00 AM] beta_helix: Hi everyone! Welcome to a Cryo-EM Density Foldit Office Hours!
[9:01 AM] Dudit: Hi @beta_helix
[9:01 AM] Susume: hi beta
[9:01 AM] beta_helix: Hi Dudit: and SusumeL
[9:01 AM] Huubr: Hi @beta_helix:. Glad I could make it, just in time :-)
[9:02 AM] beta_helix: Perfect timing! So I wanted to have a specific chat about Puzzle 1964, since it's different than anything we've ever posted before:
[9:02 AM] beta_helix: https://fold.it/portal/node/2011305
[9:03 AM] Dudit: @beta_helix: Are there a plan in Foldit to add Selenocysteine Amino Acid ?
[9:03 AM] Dudit: https://en.wikipedia.org/wiki/Selenocysteine
Selenocysteine (symbol Sec or U, in older publications also as Se-Cys) is the 21st proteinogenic amino acid. Selenocysteine exists naturally in all three domains of life, but not in every lineage, as a building block of selenoproteins. Selenocysteine is a cysteine analogue with a selenium-containing selenol group in place of the sulfur-containin...
[9:03 AM] Susume: I am loving 1964, no idea how others are finding it
[9:04 AM] beta_helix: Good question, Dudit:. We've discussed adding non-canonical amino acids before, but never pursued that idea.
[9:04 AM] beta_helix: I'm happy to hear that, Susume
[9:05 AM] Huubr: I find 1964 very interesting! I am curious how an ED map is created. Could you tell us something about that?
[9:05 AM] beta_helix: As background, we had an exciting Foldit publication demonstrating how good you all are at fitting cryo-EM models: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000472
Building de novo cryo-electron microscopy structures collaborativel...
This Community Page article demonstrates that microscopists can now collaborate with the players of the computer game Foldit to generate thorough high-quality de novo structural models; this development could greatly speed the generation of excellent Cryo-EM structures when used as a complement to current methods.
[9:07 AM] beta_helix: @HuubR That is a great question. I can briefly explain (as I am not an experimentalist) but I think with cryo-EM, it's a lot cooler (pun intended!) to see how it is created. IMO, this short 1 minute YT video is a pretty good explanation: https://www.youtube.com/watch?v=6G550DfY75Q
MRC Laboratory of Molecular Biology
Cryo-EM Animation
[9:09 AM] beta_helix: The advantage of cryo-EM over x-ray crystallography is that crystalizing proteins means you lose any movement. Cryo-EM is able to freeze a protein using liquid ethane, without creating any ice crystals. Then a bunch of 2D images are taken and reconstructed into a 3D model with computers
[9:10 AM] beta_helix: Previously in Foldit we were always able to give you a small Electron Density (ED) cloud, because we knew the answer and could easily trim the density for you.
[9:11 AM] beta_helix: (That was the case for the 4 puzzles from that paper) But this is the first puzzle where we can't provide you with that information!
[9:11 AM] Huubr: A bunch of 2D images converted to a 3D model, as in "regular" X-ray tomography?
[9:12 AM] Susume: you did once give us a big brick of cloud in which we had to choose a copy of the protein, but it was still a monomer and they were all lined up the same way
[9:12 AM] beta_helix: So the 2D images are in many different orientations, thankfully, making it easier to build a 3D model (rather than if they were all oriented the same way).(edited)
[9:13 AM] beta_helix: Yes, Susume good point. The purpose of that puzzle was to see if the tools in Foldit were sufficient, or if we needed to provide you with a trimmed map.
[9:13 AM] beta_helix: If I recall, it was thanks to that puzzle that the Trim Tool was requested and added to the game
[9:15 AM] Susume: if we get a good model of most of the protein but there are a couple of loops for which we can't match the density, is it possible to solve (or partially solve) the protein from that, or only if we get the whole thing right?
[9:16 AM] beta_helix: Great question!
[9:17 AM] beta_helix: If that is the case, we should be able to trim the density based on that "pretty darn close" model... and then we could repost it as a much easier ED puzzle.(edited)
[9:17 AM] beta_helix: At that point, we might even be able to include the RNA molecule!
[9:17 AM] Susume: I ask because the loop in the center of the donut is very hard to find a path for, as are the two tails
[9:18 AM] beta_helix: This puzzle is large enough already, that we hesitated about adding in more molecules (and slowing the puzzle down even more).
[9:19 AM] beta_helix: In that case, the RNA might help with that
[9:20 AM] Huubr: The density map that we have now has a regular pattern of (almost?) identical monomers in it. Would you know whether that periodicity can be used to enhance the resolution? In other words, can the repetition in the pattern be exploited to reduce the noise, by averaging it out? Or is that something that has already been done?
[9:21 AM] beta_helix: @HuubR Wow, that is a great question that I do not know that answer to. My assumption is that our collaborators gave us the very best map they currently have.
[9:21 AM] Susume: maybe - but I think I found the RNA, it looks to be buried fairly far from the inner donut surface, and it is the very surface I am struggling with
[9:21 AM] beta_helix: Perhaps by providing a decent model, however, they could somehow enhance the resolution (but I have no idea if that is possible).
[9:22 AM] beta_helix: @Susume I see... In that case my suggestion would be to follow the score function, and see where Rosetta believes it fits best
[9:23 AM] Susume: the repetition can be used by players - if you find a specific piece that is repeated periodically, you must fill exactly one copy of that piece with protein
[9:23 AM] beta_helix: I will be sending today's transcript to our collaborators and will let you know their feedback!
[9:23 AM] Susume: (unless you think it is the RNA in which case don't fill it)
[9:24 AM] beta_helix: Question for you all: have you been able to trim down the density to a single monomeric area (-ish)
[9:24 AM] beta_helix: to make it easier to work with?
[9:25 AM] Huubr: You mean, trim in our heads, or on the screen?
[9:25 AM] beta_helix: on the screen
[9:25 AM] Susume: in my head yes - I forgot to try using the actual trim tool ....
[9:25 AM] beta_helix: I was referring to the Radius Slider: https://fold.it/portal/node/2009618
New Release!
New Release!
[9:26 AM] beta_helix: * Added "radius" slider to electron density panel to view only electron density data within a ball of the given radius.
[9:26 AM] beta_helix: I feel like this puzzle would be so difficult without using that tool!
[9:27 AM] Susume: I tried using the sphere but then you can't see the repeats (or in my case the red dots I marked them with) to use as don't-go-here' landmarks
[9:27 AM] Huubr: I had found the Radius slider, but I would rather have an eraser :P
[9:27 AM] beta_helix: Thank you both, that is very helpful.
[9:27 AM] beta_helix: The eraser has been requested for a long time, but is not a trivial tool to implement.
[9:28 AM] Huubr: I had figured it would be difficult to implement a GUI for it.
[9:28 AM] Susume: the trim slider may be more useful - I'll work with it some. It still has the flaw of not saving your setting and not giving a number to your setting
[9:29 AM] beta_helix: @HuubR it would almost have to be its own separate component
[9:29 AM] beta_helix: @Susume Oh! That is very useful to know and shouldn't be too difficult to implement (famous last words from someone who isn't a dev can you not quicksave your current state?)(edited)
[9:31 AM] Susume: quicksaving and restoring does not restore the could trim that was in effect when you quicksaved
[9:31 AM] Susume: *cloud
[9:32 AM] beta_helix: That isn't good at all!
[9:32 AM] beta_helix: We'll see if we can fix that soon.
[9:32 AM] jmbrownlee333:In the early days and in revisiting puzzles we are given 'easier' puzzles with known answers. These have training value. Could puzzles that are easier of this type be an option? So we can learn on the 'bunny hill'
[9:33 AM] Susume: I take one thing back - reducing the sphere leaves the dots visible, just hides the cloud they are assoc with
[9:33 AM] beta_helix: @jmbrownlee333 That was our motivation for https://fold.it/portal/node/2011219
[9:34 AM] beta_helix: @ Susume thanks!
[9:34 AM] Susume: I would not mess with attaching a trim value to a quicksave - just make it like the other sliders that show their current state when you re-open them and display a number for their current setting
[9:34 AM] beta_helix: @Susume got it, that makes sense.
[9:35 AM] Huubr: Puzzle 1847 was a nice level to start with (i had been folding for 2 months then :-)
[9:35 AM] beta_helix: @jmbrownlee333 or were you referring to Revisited puzzles in general? (not specifically ED)
[9:35 AM] Huubr: (and 1847 had a very detailed map!)
[9:36 AM] beta_helix: @HuubR Ah yes, that was an awesome puzzle: https://fold.it/portal/node/2009799
[9:37 AM] jmbrownlee333:Just referring to the 'bunny hill' idea in general. I guess I meant Ed puzzles in specific.
[9:37 AM] beta_helix: We need more Foldit player designs to solve first
[9:37 AM] jmbrownlee333:But solve them with cryoEM and give us a swath of density
[9:38 AM] beta_helix: @jmbrownlee333 I completely understand. I was just worried you meant that we don't have enough Revisited puzzles up in general. But, indeed, other than the Beginner ED puzzle, and that recent last one, we rarely give you a known structure. This is easily something we can fix!(edited)
[9:39 AM] jmbrownlee333:The Beginner ED puzzle is a perfect example. Thats great training for ED puzzles in general.
[9:39 AM] beta_helix: Great, thanks!
[9:40 AM] beta_helix: Have you heard any feedback from your teammates or other players about the difficulty of this puzzle?
[9:42 AM] Susume: I have not, but I'm not as plugged in as I used to be

[9:42 AM] argyrw:hi
[9:42 AM] argyrw::)
[9:42 AM] beta_helix: Hi argyrw
[9:42 AM] argyrw: you can I learn about the bonus points all time loose bonus of that
[9:43 AM] argyrw: how can I learn
[9:43 AM] argyrw: is like blind the game
[9:43 AM] argyrw:IMAGE: http://fold.it/portal/files/chatimg/irc_936722_1615481002.png

[9:43 AM] argyrw:IMAGE: http://fold.it/portal/files/chatimg/irc_936722_1615481006.png

[9:43 AM] argyrw:this is one example
[9:43 AM] beta_helix: Protein design makes folding that much more difficult.
[9:44 AM] argyrw:yes but the bonus points give all points in the game
[9:44 AM] argyrw:like the puzzle which I play
[9:44 AM] argyrw:IMAGE: http://fold.it/portal/files/chatimg/irc_936722_1615481079.png

[9:44 AM] beta_helix: You aren't just folding and scoring the protein based on the Rosetta/Foldit score, you also need to make sure that the metrics are satisfied or else your design will simply not fold.
[9:44 AM] argyrw:hydrogen bonds network what is that?
[9:45 AM] beta_helix: This post should help you: https://fold.it/portal/node/2010984#comment-43985
[9:45 AM] argyrw:wait to try copy paste thank you
[9:46 AM] beta_helix: It addresses all the metrics, and hbonds, in one post!
[9:47 AM] beta_helix: You can also just go to the Forum and it's the top stickied post
[9:47 AM] beta_helix: scroll down to Part 6
[9:48 AM] beta_helix: Any other questions for this Foldit Office Hour? They don't have to be about ED
[9:49 AM] Susume: baker lab just had a paper about pairwise decomposable BUNS penalty - have the foldit team looked at it?
[9:50 AM] spvincent: I was wondering about Buns at the ends of helices: are they artefacts?
[9:50 AM] Susume: (I will bug bkoep too - just excited to see a filter that could possibly get incorporated in the regular score)
[9:51 AM] beta_helix: Great question, I didn't know about it but I'm sure bkoep and neil (who are both in the Baker Lab) know all about it. I will ask them about it.
[9:51 AM] Huubr: @Susume, could you briefly explain "pairwise decomposable BUNS penalty" to a regular Foldit player?
[9:52 AM] beta_helix: @Susume my guess is that it's probably in a very recent version of Rosetta, so it will require Foldit merging with the latest code. That is non-trivial, but is on the horizon with the new small-molecule design features that are coming.
[9:52 AM] Susume: BUNS in foldit have to be a filter (not part of regular score function) because it depends on groups of AAs, not just on pairs of AAs (everything in regular score has to be a measure of one AA or of a pair)
[9:53 AM] beta_helix: Oh dear, I knew as soon as I said "non ED stuff is ok to ask" I would be flooded with design questions
[9:53 AM] beta_helix: @spvincent I don't want to give you the wrong answer, so I will ask the team today about this
[9:53 AM] Susume: a baker lab scientist figured out a way to calculate BUNS penalty and assign it to pairs of AAs - which might make it possible to put into regular score - then it will play better with scripts, be more continuous, etc
[9:54 AM] Huubr: Thanks, @SusumeL, I am getting the picture (I think).
[9:54 AM] beta_helix: argyrw will be happy about that as well, Susume!
[9:55 AM] spvincent: tx
[9:55 AM] jmbrownlee333:non science question. Will we ever get the promisec new website? Do ya know anything about that perchance?
[9:55 AM] Susume: best thing about putting it in score is then wiggle tool can 'see' it and optimize it at the same time as other score parts - wiggle does the cost/benefit work instead of us
[9:55 AM] jmbrownlee333: promised
[9:55 AM] Josh: jmb I can answer this one -- we are actively developing and testing it
[9:55 AM] jmbrownlee333:ETA?
[9:56 AM] Josh: The delays are due to a bottleneck of developer time -- UW keeps stealing our dev :P
[9:56 AM] jmbrownlee333:I see
[9:56 AM] Josh:Unfortunately, I don't have an ETA :/ all I can say is soon
[9:57 AM] beta_helix: I would guess that at the end of this month, start of next month, you should see a "devprev" version of it (just my guess)
[9:57 AM] beta_helix: @ Susume yes indeed, we always want to include as much as possible in the actual score function!
[9:58 AM] beta_helix: any last questions for Josh or I?
[9:58 AM] Susume: oo, in honor of Formula, anything you wish players would do more of, or do less of?
[9:59 AM] beta_helix: I usually give the same answers, for design: try to submit as many solutions that meet all the metrics as puzzle, etc.
[9:59 AM] beta_helix: But today I'll say: tell your friends about Foldit.
[10:00 AM] Huubr: Got no more questions right now. I will try and collect some thoughts about image enhancement, and put them in a PM, if that's OK?
[10:00 AM] beta_helix: @HuubR of course!
[10:00 AM] beta_helix: This might seem silly for the many of you that have been around for so long... but I think Josh: has done some amazing work in Foldit
[10:01 AM] beta_helix: Making the game a lot more accessible to new players. So, hopefully when the new website is settled, it'll be easier to keep interested new players. Just my 2 cents
[10:01 AM] Josh: @ Susume my request, as usual, is for anyone who's been playing more than 6 months to find a way to share their knowledge -- on the wiki, a guide on the forums, anything
[10:01 AM] Susume: yes he has!! so grateful for Josh!
[10:01 AM] Josh: <3 !!
[10:01 AM] beta_helix: Just look at the Forum post I was able to give argyrw earlier!
[10:02 AM] beta_helix: Normally I'd frantically be searching for the news posts or wiki pages!!!
[10:02 AM] Huubr: https://fold.it/portal/node/2010984#comment-43985
[10:02 AM] jmbrownlee333:I second SusumeL's thought
[10:02 AM] Josh: That How to Foldit guide was 92 pages long in a google doc...
[10:02 AM] Josh: glad it's helpful :)
[10:02 AM] Huubr: Me too (or would that make three? ;-)
[10:03 AM] beta_helix: On that note (Josh: rules!) I'll end with: Thank you all for chatting today, thanks for playing that giant ED puzzle, and thanks for the great folding that you do! Keep it up!

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hour 3/27/21- led by Neilpg628

[11:01 AM] neilpg628: Hello All, its @neilpg628 , ready to answer some questions!!
[11:01 AM] Dudit:Hello @neilpg628
[11:02 AM] pc: hi
[11:02 AM] cjddig: Hello, it's my first time to attend the Office Hour.
[11:02 AM] pc: @neilpg628 : In the 1968 puzzle, BUNS never appeared on the player's protein, only on the virus Amino Acids. was it a bug or was it a voluntary setting ?
[11:03 AM] neilpg628: Do you mean 1966?
[11:04 AM] pc: 1968 "Influenza HA Binder Design Competition"
[11:05 AM] neilpg628: That could have been an issue. but I only deal with the rigid linker puzzles so I'm not sure
[11:05 AM] Dudit: @neilpg628 Why Foldit is always have a lag/latency (especially when there is a lot of Objectives) ?
[11:05 AM] pc: ok thanks ^^ @Dudit
@neilpg628 Why Foldit is always have a lag/latency (especially when there is a lot of Objectives) ?
[11:06 AM] neilpg628: The scientific backend of Foldit is 3 million lines of Rosetta C++ that is installed as a bunch of binaries on your machine The code is not optimized for gameplay and is meant to run on large clusters or distributed computing projects like Rosetta@home Thus it can be quite slow to do a lot of the expensive computations necessary on your machine alone
[11:07 AM] Dudit: Thanks
[11:08 AM] cjddig: I often experience a lot of lags in the ED puzzle. Does ED cloud causes lags or is the performance of my computer not good? Is there a way to reduce the lags?
[11:09 AM] neilpg628: It is probably the ED cloud We are working on ways to make the computation of coordinates less intensive I don't think computer performance is relevant since we are trying to make a game for a huge range of platforms and configurations
[11:09 AM] pc: @neilpg628 When I mutate a starting protein (like a tripple helix), there is often Treonine that appear on core. I think it is maybe because some helixes are too close sometimes, but it happen often. Should I keep them, or why "mutate" choose them instead of a "good" hydrophobic sidechain ?
neilpg628: It is probably the ED cloud We are working on ways to make the computation of coordinates less intensive I don't think computer performance is relevant since we are trying to make a game for a huge range of platforms and configurations
[11:09 AM] cjddig: OK, Thanks
[11:11 AM] pc: (so I fix thoses threonines with hand folding + wiggle often)
[11:14 AM] pc: oh he is disconected I think
[11:14 AM] donuts554: hello
[11:16 AM] HuubR: @pc, which residues do you have in your helices before mutate? When you start with Alanine, you are likely to get your helices very close together.
[11:17 AM] alcor29: There appears to be a UWIT outage.
[11:18 AM] neilpg628: How do you mean?
[11:18 AM] alcor29: oh you're bak.
[11:18 AM] neilpg628: I never left lol
[11:18 AM] neilpg628: I was just waiting
[11:20 AM] nspc: IMAGE: http://fold.it/portal/files/chatimg/irc_959223_1616865644.png

[11:20 AM] nspc: sometilmes I just start like this
[11:21 AM] cjddig: Another question: What is the criterion of the invalid residues? Alanine is good to make the core, but many puzzles consider it as invalid residue.
[11:21 AM] nspc: IMAGE: http://fold.it/portal/files/chatimg/irc_959223_1616865717.png

[11:22 AM] Dudit: @neilpg628 Is there a plan from the Foldit Developer Team to further optimizing Foldit to greatly reduce lag?
cjddig: Another question: What is the criterion of the invalid residues? Alanine is good to make the core, but many puzzles consider it as invalid residue.
[11:24 AM] neilpg628: Rosetta intrinsically favors some residue types over others ALA is one of these and if it was unrestricted then the most energetically favorable configuration would just be a bunch of ALA which would not be good
Dudit: @neilpg628 Is there a plan from the Foldit Developer Team to further optimizing Foldit to greatly reduce lag?
[11:24 AM] neilpg628: There are some optimizations that can be done but a lot of it is on the Rosetta side which is harder to change
neilpg628: Rosetta intrinsically favors some residue types over others ALA is one of these and if it was unrestricted then the most energetically favorable configuration would just be a bunch of ALA which would not be good
[11:25 AM] cjddig: Thanks
[11:25 AM] donuts554: How strong are the hydrogen bonds involving sulfur compared to pi stacking?
[11:26 AM] neilpg628: Pi stacking is probably weaker since Hbonds form the majority of electrostatic interactions
[11:27 AM] pc: To create a first stable protein alone in a design puzzle (or linker), I use the Building Blocs, Ideal SS... I worked on the core first (selecting only core) with mutate core only, and global wiggles. It seems to me that we should not mutate sidechain outside the protein at begin, because the bouds which are made could distort the protein too much when I wiggle. So I mutate outside only at end, when core it stable. Do you think that's ok, or is it better to mutate and wiggle all the protein each time ?
[11:29 AM] donuts554: But in the Foldit puzzles I dont see hydrogen bonds involving sulfur
[11:30 AM] donuts554: Why arent hydrogen bonds involving sulfur shown in the Foldit puzzles?
donuts554: Why arent hydrogen bonds involving sulfur shown in the Foldit puzzles?
[11:30 AM] neilpg628: Did you mean disulfides?
[11:30 AM] neilpg628: Those are chemical bonds and would be stronger than any Hbond or Pi stacking
[11:31 AM] donuts554: Not just disulfides
[11:31 AM] cjddig: Is sulfur polar atom which can make HBonds? I assume he is saying this.
[11:31 AM] neilpg628: I don't think sulfur can make Hbonds Not sure though
[11:32 AM] donuts554: Oh ok
[11:32 AM] donuts554: I think you forgot to answer Dudit:'s and pc's questions
[11:32 AM] jmbrownlee333: I think S-H covalent bonds engage in very weak hydrogen bonds and can thus be disregarded.
pc: To create a first stable protein alone in a design puzzle (or linker), I use the Building Blocs, Ideal SS... I worked on the core first (selecting only core) with mutate core only, and global wiggles. It seems to me that we should not mutate sidechain outside the protein at begin, because the bouds which are made could distort the protein too much when I wiggle. So I mutate outside only at end, when core it stable. Do you think that's ok, or is it better to mutate and wiggle all the protein each time ?
[11:34 AM] neilpg628: I think your strategy is fine Too much mutation can prevent any real structure from forming
[11:34 AM] pc: thanks
[11:35 AM] donuts554: But how weak are the weak hydrogen bonds that S-H covalent bonds engage in compared to pi stacking and the "Cation-Pi Interaction"?
[11:36 AM] neilpg628: I don't know the specific bond energies but they might be similar @bkoep might know for sure
[11:37 AM] pc: @neilpg628 In a design puzzle, player protein need hydrophibics that touch the virus (to stay in place). But if there is too much hydrophobics outside the player protein, it can have problems to fold alone. How many hydrophobic can we have outside, is there a metric for this that will be done ? Or it is a too much complex prediction to do (and maybe we will need "alpha fold" ?) If there are spaced enough do you think it is better ?
[11:38 AM] pc: (sorry for my long questions ^^ )
[11:39 AM] donuts554: But bkoep said that he didnt know that answer at the top of his head at a previous office hour
[11:40 AM] neilpg628: I'm not a biochemistry student so you might have to look around ¯\_(ツ)_/¯
[11:41 AM] donuts554: Oh ok then
pc: @neilpg628 In a design puzzle, player protein need hydrophibics that touch the virus (to stay in place). But if there is too much hydrophobics outside the player protein, it can have problems to fold alone. How many hydrophobic can we have outside, is there a metric for this that will be done ? Or it is a too much complex prediction to do (and maybe we will need "alpha fold" ?) If there are spaced enough do you think it is better ?
[11:43 AM] neilpg628: I agree that too my hydrophobics is bad for folding but ideally the surface is mostly hydrophobic with a few polars that can hbond with polars on the binders for specificity The ContactMS and Core Exists Objectives try to capture some of this behavior.
[11:44 AM] Dudit: @neilpg628 In puzzle 1968 (Binder Design Competition), where are the final rankings?
[11:44 AM] pc: thanks. One of my strategy is to use hydrophobics that protrude from the core as possible
Dudit: @neilpg628 In puzzle 1968 (Binder Design Competition), where are the final rankings?
[11:45 AM] neilpg628: Are they not on the website?
neilpg628: Are they not on the website?
[11:46 AM] Dudit: I mean the total valid submission to the Scientists
[11:47 AM] neilpg628: I'm not sure what you mean but the puzzle only closed yesterday so they might still be being processed
[11:48 AM] donuts554: When will colored text in the Recipe Output dialog box be added to Foldit?
donuts554: When will colored text in the Recipe Output dialog box be added to Foldit?
[11:48 AM] neilpg628: @Josh might know
[11:49 AM] alcor29: What are you currently working on neil?
[11:50 AM] neilpg628: My focus is the BUNS and DLP stuff(edited)
[11:50 AM] donuts554: Oh ok
[11:50 AM] alcor29: DLP?
[11:50 AM] neilpg628: The Designable Linker stuff
[11:51 AM] pc: @neilpg628 : In linker puzzles one of he main difficulty is to join the last cutted point (and keep ideality) do you plan to do a new tool to help for it ? there is some strategies (using band on helix), but it is still difficult.(edited)
[11:51 AM] donuts554: Oh wait I found a problem with the BUNS objective
[11:51 AM] donuts554: I remember that it was on a symmetry puzzle
[11:52 AM] donuts554: Yes it was on Puzzle 1954
pc: @neilpg628 : In linker puzzles one of he main difficulty is to join the last cutted point (and keep ideality) do you plan to do a new tool to help for it ? there is some strategies (using band on helix), but it is still difficult.(edited)
[11:53 AM] neilpg628: What sort of tool would be helpful?
[11:53 AM] donuts554: The BUNS objective in 1954 is not consistent, as 4 BUNS suddenly pop up from 0 BUNS when I rotate my green protein, and my green protein is far away from the other three locked proteins
[11:54 AM] pc: maybe when we try to join a cutted point, have a different representation of the 2 parts. To help us to know it is will be ok.
[11:54 AM] donuts554: And I rotated by left-clicking on the protein, and by dragging the purple arrow about 7 degrees clockwise
[11:55 AM] nspc: IMAGE: http://fold.it/portal/files/chatimg/irc_959223_1616867704.png
[11:55 AM] nspc: IMAGE: http://fold.it/portal/files/chatimg/irc_959223_1616867736.png
[11:56 AM] nspc: it is often bad when we join the last cutted point like this
[11:56 AM] nspc:(in linker puzzles)
[11:56 AM] Susume: I think donuts may be running into the voxel issue
donuts554: The BUNS objective in 1954 is not consistent, as 4 BUNS suddenly pop up from 0 BUNS when I rotate my green protein, and my green protein is far away from the other three locked proteins
[11:56 AM] neilpg628: This is a known issue unfortunately Basically the calculator used to compute surface area is sensitive to rotation of the structure even with no change This means that atoms can be flagged as 'buried' or 'not buried' depending on their orientation which affects the BUNS count
[11:58 AM] cjddig: How BUNS affect real protein? Why are they bad for protein?
[11:59 AM] Josh: donuts554 colored recipe text is currently a low priority because not many players are saying it would really benefit their play. If more players tell me they really want this feature, I can make it a higher priority.
[11:59 AM] Josh: *recipe output text
[12:00 PM] donuts554: Ok so thats why I dont want to play puzzles with the BUNS objective in them as much
[12:00 PM] donuts554: Oh ok Josh
[12:00 PM] Susume: pc I have a suggestion: make a new cut in the middle of a helix, then heal the cut in the loop, and use ideality or blueprint to make the loop healthy. Then you can work on healing the cut in the helix using bands - it is much easier in the middle of the helix to see if the shape will be good
cjddig: How BUNS affect real protein? Why are they bad for protein?
[12:00 PM] neilpg628: The blog post here might help They can prevent the protein from folding because these atoms would rather bind with water than remain buried https://fold.it/portal/node/2009053
The BUNS Objective
The BUNS Objective
[12:00 PM] donuts554: Also Neil what things do you want to encourage Foldit players to do, and what things do you want to discourage Foldit players to do?
neilpg628: The blog post here might help They can prevent the protein from folding because these atoms would rather bind with water than remain buried https://fold.it/portal/node/2009053
[12:00 PM] cjddig: Thanks, I'll look into it.
[12:01 PM] Skippysk8sIRC: In last puzzle with buns, I couldn't easily mutate the "mutatable" side chain on the frozen SS. I ended up using Maaaa on one segment, which seemed very slow
[12:01 PM] Skippysk8sIRC: Any better ideas?
[12:02 PM] alcor29: Linking LCB seems to intiuitively cut down the chances of bonding to the targer. Is the precise angle we use derived from the distribution on targets on the virus sphere? And are these targets symmetrically distributed like the tetrahedral bonds of a Carbon atom?
[12:02 PM] pc: thanks susume. I already tryed, it is not very easy but can works yes. I try to think about a tool that make the puzzle easier for the most people too ^^.
alcor29: Linking LCB seems to intiuitively cut down the chances of bonding to the targer. Is the precise angle we use derived from the distribution on targets on the virus sphere? And are these targets symmetrically distributed like the tetrahedral bonds of a Carbon atom?
[12:07 PM] neilpg628: The angle is pretty accurate and we took it from a very precise crystal structure of the actual binding complex
[12:07 PM] neilpg628: Thanks for all the questions!

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hour 4/18/21- led by Jflat06

1:59 PM] jflat06: Hello
[1:59 PM] pc: @jflat06 first question : how are the new features that are made for foldit decided? scientific needs, players sugestions, intern testing, other things ?
[2:00 PM] jflat06: @pc: pretty much a mix of those things! But our priorities usually place a premium on scientific needs
[2:00 PM] jflat06: usually shortly followed by issues involving the integrity of the competition
[2:01 PM] pc: thanks
[2:01 PM] jflat06: Then we like to tackle high-value features, whether they be player suggestions or otherwise
[2:02 PM] jflat06: One of the things that makes foldit pretty interesting/unique is that we have 4-5 different labs around the country all collaborating on the project, and each them has their own priorities and vision of how to use foldit
[2:03 PM] donuts554: hello
[2:03 PM] jflat06: hi
[2:03 PM] cjddig: When does new Foldit website come out? What is advanced or new features it has?
[2:03 PM] donuts554: Hello how are you?
[2:04 PM] jflat06: The website should hopefully be coming out within the next month, at least to a test site that players can play with. We're at the stage where we're reviewing the code to make sure its all good, and fixing/implementing some missing features.
[2:05 PM] jflat06: The biggest of the new features is that the Recipes system has been reworked.
[2:05 PM] dudit: @jflat06 When does 64-bit Foldit Windows version come out?
[2:06 PM] jflat06: @Dudit its not currently a priority since it isn't actually actively causing issues. We plan on doing it eventually, but there's not a strong incentive to work on it over our other tasks.
[2:06 PM] alcor29: Can you talk some about the new Recipes system?
[2:07 PM] jflat06: For any of you in discord, I am in the livestream channel (muted) sharing my screen with the new recipe system demo
[2:08 PM] jflat06: The gist of it is that the recipes are now primarily edited through the website.
[2:08 PM] jflat06: And you can maintain a library on the website that will refresh your client recipe list with the click of a button.
[2:08 PM] jflat06: I'll go ahead and make a new recipe now
[2:09 PM] dudit: @jflat06 I think it will be great if we can Pause a recipe
[2:09 PM] HuubR: You mean, pause and do some hand folding, and then continue the recipe where it was paused?
[2:10 PM] jflat06: I'm not quite sure what is involved in that, but it's something we can consider.
[2:10 PM] jflat06: It's sort of out of the scope of the stuff I'm working on right now, though.
[2:10 PM] jflat06: Also included in this, for people who prefer to work locally, you can now load/run a recipe from a raw text file.
[2:11 PM] LociOiling: you might want to mention that GUI and Lua V1 recipes are going away...
[2:12 PM] pc: @jflat06 In projects the devs know the project well, but not always from a player's point of view. Is the foldit team use foldit often as a player ? We can give you more feedbacks to whatch us play and to better understand our needs, or mistake we do.
[2:12 PM] jflat06: Right, we're retiring GUI/lua v1 recipes as part of this, as it makes the data transfer to the new site much cleaner.
[2:12 PM] Susume: when our recipes live on the server, the scientists can look to see if we have invented any cool algorithms - if we run locally from text file, will foldit team still be able to see the recipe?
[2:12 PM] LociOiling: what happens to GUI and Lua v1 recipes in someone's cookbook? do they disappear, or just not run?
[2:13 PM] jflat06: @Susume they will not, which is why we prefer them on the website. But we thought it was important to include support for local work as well.
[2:14 PM] Susume: ok
[2:14 PM] jflat06: @LociOiling The actual (old) cookbook file will remain on your computer, but they will not appear in the new recipe library.
[2:15 PM] jflat06: We are considering trying to auto-convert old recipes, but it isn't necessarily easy, especially for the GUI ones.
[2:15 PM] Skippysk8sIRC: so will we have to reload our cookbooks again
[2:16 PM] jflat06: @pc Some of us play (more than others). We do make an effort to understand the point of view of the players, though.
[2:16 PM] alcor29: If GUI recipes wont work anymore can you autodelete them from our cookbooks?
[2:17 PM] Skippysk8sIRC: or better still autoconvert lol
[2:17 PM] jflat06: @skippy You'll configure your new cookbook once on the new site, and then it'll just be a matter of pressing "refresh library" in whatever client you want your library to show up.
[2:17 PM] jflat06: Unfortunately since the idea of a cookbook only exists locally currently, we don't have any way of moving that over to the server.
[2:18 PM] LociOiling: ok, sounds like all.macro is a thing of the past once the new system is up
[2:18 PM] pc: ok. I can do more feedbacks if needed in video). I have some things to show, and there is multiple possible solutions.
[2:18 PM] jflat06: It won't autodelete them, but they will not show up in the new cookbook. You can delete your old all.macro if you want to nuke them off your disc :0
[2:18 PM] jflat06: @LociOiling Yes!
[2:19 PM] jflat06: Recipes are now stored in a 'recipes' folder, and there's 1 file per macro now.
[2:19 PM] jflat06: When you click 'refresh' in the client, it will download any new/changed recipes to make sure you have the latest stuff from the website
[2:20 PM] Skippysk8sIRC: so if we have personal settings we save (e.g. sheet bands sets all bands for sheet bonding) we have to share to public now?
[2:20 PM] jflat06: You'd create a copy on the website. Whether it is shared or not is up to you
[2:21 PM] jflat06: You can make it totally unshared (wont even show up in your own library in-client), self shared, group shared, or public shared.
[2:21 PM] Skippysk8sIRC: kk
[2:21 PM] LociOiling: sounds good so far, avoids copying all.macro all over the place
[2:21 PM] jflat06: We have some neat ideas with creating leaderboards or competitions for recipe writers, but those are all in early development
[2:21 PM] jflat06: But I do want to stress that people who prefer to code locally can still do so - and better than before.
[2:22 PM] jflat06: We decided that an in-client text editor was more of a liability than a feature, so we're just letting you write up the recipes in the editor of your choice, and then simply run the recipe from the file.
[2:23 PM] cjddig: Something went wrong, and I couldn't see the streaming, but question: Will it provide syntax highlighting?
[2:23 PM] jflat06: The website interface does have syntax highlighting
[2:23 PM] jflat06: if you're coding locally, you can use any editor you want.
[2:24 PM] jflat06: (sorry, Discord probably isn't the best place to demo features, especially while I'm trying to chat here at the same time)
[2:24 PM] jflat06: @LociOiling yeah that was a big motivator. It also lets us more accurately track who's using what, so we can get a better idea of which things are good.
[2:25 PM] jflat06: Which also should hopefully help us do a better job at recommending or highlighting recipes to new players
[2:25 PM] alcor29: Will the recipe web listing be more sortable than our cookbooks are now? e.g. I may not want alphbetical order etc. ?
[2:26 PM] jflat06: We're still working on that interface, but I'm thinking it should be.
[2:26 PM] jflat06: There's already a search feature, which is much nicer.
[2:27 PM] alcor29: great
[2:28 PM] dudit: @jflat06 Will the recipe sorting include the most downloaded / most used recipe?
[2:29 PM] donuts554: Will images be able to be used in the Foldit Website Forum and Feedback posts?
[2:29 PM] jflat06: We want to provide multiple ways of ensuring players are finding the recipes that are most useful to them. Most downloaded/used are pretty good metrics, so those will probably be included
[2:29 PM] alcor29: Most correlated with high ranking would be super.
[2:30 PM] jflat06: @donuts currently on the test site I don't think there's a direct ability to do that, but I am looking into being able to include them more easily.
[2:30 PM] pc: @jflat06 Do we have somes news about Mers puzzles lab tests ? Bkoep talked about soon results there is some months. If it didn't worked, do we know why ? (it is useful for us to adapt how we play)(edited)
[2:31 PM] jflat06: I'll leave that to bkoep as he's more informed about the current state of those results. I will say that the actual physical lab part of biochemistry is a very long process.
[2:32 PM] pc: thanks
[2:32 PM] jflat06: We try and make players aware of results when we think we have a reasonably certain answer to give
[2:32 PM] pc: we are interested by why it didnt work too ^^
[2:33 PM] jflat06: yup! definitely
[2:34 PM] dudit: @jflat06 Will the recipe sorting include a category (example: Early; Early-Mid; Mid; Mid-End; End) ?(edited)
[2:34 PM] jflat06: @Dudit Not currently, but I'm hoping to add a 'tag' system that could be used for that, and more
[2:35 PM] jflat06: Some of these features may come after the fact. Right now we're focusing on the core systems that we cant easily change once things are deployed.
[2:35 PM] alcor29: Most correlated with low rankings also useful.
[2:36 PM] jflat06: @alcor29 a cool idea would be making the recipes and associated data available to everyone, so people could do their own sorting
[2:36 PM] jflat06: But I just came up with that idea right now, so no promises
[2:36 PM] alcor29: Yup
[2:37 PM] Skippysk8sIRC: Folding styles vary --- I'm not sure that all recipes fit a game stage nor that we want to direct players to use them that way. Sometimes different approaches can yield equally good results from different processes
[2:37 PM] jflat06: One of my areas of interest is in taking player-generated content and finding the most effective way to filter it to show only the relevant stuff to other players.
[2:37 PM] jflat06: Lots of games have this problem, and lots of them have some not-so-great systems for dealing with it
[2:38 PM] donuts554: But I think that some Foldit Players could maybe skew the recipes to have them be unfairly correlated with low rankings
[2:38 PM] jflat06: @skippy I agree. It would probably end up functioning something like Steam's tag system, where it is a product of community consensus
[2:38 PM] LociOiling: will links to the old website still work, getting redirected to the new?
[2:38 PM] jflat06: @LociOiling Yeah, that's something that we've talked about, and I think it's handled.
[2:39 PM] jflat06: There might be some links that dont have corresponding pages in the new website, though.
[2:39 PM] alcor29: Results (rankings) seem to be the most important and objective measure.
[2:39 PM] cjddig: How about suggestion feature, that analyzes the recipes someone used and suggests the recipes similar to them?
[2:40 PM] pc: @jflat06 Perhaps the frequently used "recipes" could become tools in GUI. I had thought for example of functions like "mutate" which would be configurable with a UI to add options (like a white list, or special rules)
[2:40 PM] jflat06: @cjddig I think there's actually people working on similar systems in some of the other games we make. It's definitely an idea we've talked about.
[2:41 PM] jflat06: @pc Yup, that's an idea we've talked about, too.
[2:41 PM] jflat06: I'd love for players to be able to add first-party buttons for third-party recipes.
[2:41 PM] pc: player often use recipes instead of hand foldit and expect recipe will do most of the job. Maybe some faster task recipes can encourage more interactivity too ^^.
[2:41 PM] jflat06: (I'll be right back in one minute)
[2:42 PM] donuts554: Why are five Foldit Contests shown to have a Start Date of January 1st, 1930?
[2:43 PM] pc: one of the drawbacks of recipes is that they seek a final solution. Maybe we also need to calculate intermediate solutions, like proteins with only core mutation at the beginning for example.
[2:43 PM] jflat06: I think that date is our "far in the future" date
[2:43 PM] jflat06: Not sure about those specifically
[2:43 PM] pc: (I though of it for linker puzzles for exemple)
[2:44 PM] dudit: @jflat06 I think Batch Running Recipes (Turning Recipes into Actions) will be a great feature
[2:45 PM] Skippysk8sIRC: @Dudit I think Constructor can do that now
[2:45 PM] Skippysk8sIRC: and it is a good idea once hand folded
[2:46 PM] cjddig: Is there any special reason that the programming language of recipe is Lua?
[2:47 PM] jflat06: I think lua is one of the more easily integrated languages for games seeking a scripting language accessible to players.
[2:47 PM] jflat06: But the decision to use lua actually predates me, so I can't say for sure
[2:48 PM] pc: Yea, I have multiple ideas for that ^^(edited)
[2:48 PM] jflat06: I think there's some pretty exciting stuff we can do for showing/recommending recipes to players, especially with the new data about who's using what
[2:49 PM] pc: it can be a simple "graphic programming", but there is more adapted solutions I think.
[2:49 PM] jflat06: But aside from recipes, there's also some other cool features coming with the new site.
[2:50 PM] alcor29: Movable windows?
[2:50 PM] jflat06: One is that when a scientist like bkoep wants to talk about one of your solutions, instead of taking a screenshot and uploading it and trying to describe some feature of a player model... we can now show you the 3D model of any solution in the browser with a link!
[2:50 PM] maithra: @jflat06 Can you give an example how to recommend recipe for symmetric design/electron density/ revisiting type of puzzles?

[2:51 PM] pc: the most important is to identify when players have difficulties, and create tools for that. In design puzzles : create the first structure and make sure it fold with a good core is not so easy. So all player make a tripple helix. off course it is difficult to have large contact zone without buns and not too much hydrophobics.
[2:51 PM] Susume: ooo, can we spin the 3D model you are showing us?
[2:51 PM] jflat06: @maithra I think that's going to come down to a system for evaluating the recipes usefulness in certain contexts
[2:51 PM] jflat06: @Susume yup!
[2:51 PM] HuubR: Cool!
[2:51 PM] cjddig: I'd better turn on my computer... I wanted to see it.
[2:52 PM] pc: oh nice
[2:52 PM] dudit: Great!
[2:52 PM] jflat06: It's a really neat system, and we might expand it in the future to possibly even let players share links to their designs on the website.
[2:52 PM] Susume: @cjddig not showing us right now, it is coming in the new website
[2:52 PM] jflat06: The biggest issue with the system is that it makes it super easy to grab the raw PDB if one is so inclined.
[2:53 PM] jflat06: So to start with, we are going to carefully limit when/where it is used.
[2:54 PM] Susume: yeah, exposing pdbs is suboptimal
[2:54 PM] alcor29: Will the top designs be showed in 3D?
[2:54 PM] jflat06: Unfortunately with the javascript 3D viewers, they need the raw PDB on-hand in the browser in order to display it.
[2:55 PM] jflat06: @alcor29 we are still figuring out the details, but that may be a possibility we consider.
[2:56 PM] jflat06: We've typically been very strict about limiting the amount of info people can put into or pull out of the game, so this is a bit of a change in tune for us, and we're trying to make sure it's all still consistent with our mission and goals.
[2:56 PM] donuts554: What is one thing that you encourage Foldit Players to do, and what is one thing that you discourage Foldit Players to do?
[2:56 PM] alcor29: It would have considerable heuristic value.
[2:56 PM] jflat06: The biggest one is... make more designs!
[2:57 PM] HuubR: Would it be possible (and, would it help) to make a sort of copy-protect feature in Foldit that will recognise a known PDB structure, and exclude it from the competition?
[2:57 PM] alcor29: Pictures and videos can teach a lot more than words.
[2:57 PM] jflat06: Our recent competition that bkoep ran had some super interesting results, and we're looking to implement it as a more formal system with the new site.
[2:58 PM] jflat06: And on that same note, something we discourage (at least scientifically) is heavy drilling, as it isn't terribly useful to use.
[2:58 PM] jflat06: @HuubR for sure, but that is a very hard problem. Especially for prediction puzzles where the whole point is to find the one native solution
[2:58 PM] jflat06: @alcor29 I agree!
[2:59 PM] Skippysk8sIRC: but "heavy drilling" for team competition is some of how we players have fun in last day. Diversity is more likely to start with hand folding at start -- fun from taking a team's best design and going for it last day or two
[2:59 PM] jflat06: That was part of my inspiration for trying to move more of the recipe stuff to the website as well. I want players to be able to share their recipes with a direct link to a website page where they can show each other their code and have conversations about it.
[2:59 PM] Skippysk8sIRC: points can be motivating, if not of scientific value
[3:00 PM] jflat06: @skippy yup, I agree. That's definitely something we take into consideration.
[3:00 PM] pc: I suppose new metrics will be added to design puzzles ?(edited)
[3:01 PM] pc: we are still uncertain whether the protein folds well in lab.
[3:02 PM] jflat06: Probably. We are getting to the point where a lot of the top designs coming out of foldit are looking pretty good, so it is starting to become more of an issue of coming up with lots of them instead of improving them.
[3:02 PM] jflat06: so are we! its a very hard problem. Even the scientists making them using their own software have a pretty low hit rate for designs that fold well in the lab.
[3:02 PM] jflat06: Which is part of the reason that having a large variety is very important.
[3:02 PM] alcor29: Will the newfoldit be faster?
[3:03 PM] jflat06: the new site? I think so
[3:03 PM] donuts554: That is good
[3:03 PM] jflat06: I've done some stress testing, but you never know until you actually deploy it
[3:03 PM] dudit: @jflat06 I think every Foldit puzzle should be a competition puzzle
[3:04 PM] pc: alpha fold metric soon (i hope )(edited)
[3:04 PM] cjddig: Newsletter page takes so much time to load all images. I hope this would be improved.
[3:05 PM] donuts554: Me too
[3:05 PM] jflat06: not quite alphafold, but we have our own version of a machine learning algorithm that we're looking to include as a metric that we hope will be very useful!
[3:05 PM] dudit: @jflat06 With a realtime total number of puzzle submitted
[3:05 PM] pc: oh interesting !
[3:06 PM] jflat06: @Dudit We're not quite sure about for every puzzle, but we are planning to have a full-featured system for these competition puzzles.
[3:06 PM] jflat06: With realtime results!
[3:07 PM] alcor29: Ah using AI algorhythm to solve buns and loops would be great!
[3:08 PM] jflat06: I think it would probably be a supplement to those (especially since it is likely to be quite a bit slower than them)
[3:08 PM] jflat06: but we're still figuring out to best integrate it, and there are some technical hurdles as well.
[3:10 PM] donuts554: Oh ok
[3:11 PM] alcor29: Thanks Jflat. Informative meeting.
[3:12 PM] dudit: Thank you very much @jflat06
[3:12 PM] jflat06: But in any case, you'll all have to thank @Susume for doing a lot of the leg work to take the underlying Rosetta machine learning algorithm and make it intelligible to Foldit players!
[3:12 PM] HuubR: Three cheers for @Susume!
[3:12 PM] dudit: Thanks so much @Susume
[3:12 PM] alcor29: Yes. Thanks @Susume.
[3:12 PM] donuts554: Thanks Susume!
[3:12 PM] pc: thanks
[3:13 PM] Susume: glad to do it!!
[3:13 PM] jflat06: Thanks for the great questions, everyone I am going to take off and get a proper lunch, now.
[3:13 PM] cjddig: Thanks both jflat06 and Susume, time to do my homework...
[3:13 PM] Susume: thanks jflat
[3:13 PM] pc: thanks jflat

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Foldit 13th Anniversary Science Chat

[2:30 PM] beta_helix: Happy birthday! We'll start the birthday Science chat in a couple minutes
[2:30 PM] Ridick051: oh 13th thanks god it's no FRIDAY
[2:30 PM] Dudit: Hi @beta_helix
[2:31 PM] Ridick051: ok hello @beta_helix
[2:31 PM] Ridick051: ^^
[2:32 PM] milkshakeiii: Woo
[2:32 PM] jflat06: Hello everyone!
[2:32 PM] bkoep: Hi all!
[2:32 PM] Ridick051: hi ^^
[2:32 PM] Dudit: hi @milkshakeiii @jflat06 @bkoep
[2:32 PM] maithra: is it question time yet?
[2:33 PM] beta_helix: YES! Hi everyone! We want to start by thanking you all for coming today, and thanking those who couldn't make it to the party. Foldit would never had made it 13 years without you
[2:33 PM] beta_helix: Fire away maithra
[2:33 PM] maithra: I copied over the previous AA and structure information from the previous 1971 symmetric Tetramers - Hbond networks into the current 1989. I used wiggle and shake, but I never got even near to the shape that I had in the earlier version. What should I do to get the similar shape of the protein when aa and structure are the same?
[2:34 PM] maithra: residue number is the same
[2:34 PM] milkshakeiii: in some puzzles, you are allowed to load solutions from previous puzzles
[2:34 PM] milkshakeiii: but in other puzzles, we want people to start from scratch
[2:35 PM] sethcooper: hello!
[2:35 PM] Dudit: hi @sethcooper
[2:36 PM] ZeroLeak7: hi @sethcooper
[2:36 PM] milkshakeiii: hi @sethcooper
[2:37 PM] rmoretti: Maithra, one thing to keep in mind is that the energy landscape is rugged. Even if you're "close", wiggle and shake may not take you to where you want to be. You may need to use a number of rubber bands to encourage the structure to go where you want it to.
[2:37 PM] josh: hi @sethcooper
[2:38 PM] jflat06: Also note that we don't always want you to re-create an existing fold - we prefer new folds - especially on Design puzzles. Diversity is important, because we need not just good folds, but many of them.
[2:38 PM]
maithra: thank you, rmoretti. What will be the rubber band in the wet lab when you are trying to create the protein? These proteins should fold up without extra help, right?
[2:38 PM] ZeroLeak7: sooo many work with rubber bands and freezing to hold the structure and wiggle and shake etc.
[2:39 PM] beta_helix: Everyone, feel free to fire off a question as there are many of us that can answer in parallel
[2:40 PM] rmoretti: The issue is that Foldit is not a perfect representation of what happens in the wet lab. Rubber bands don't correspond with anything in the wet lab, but rather they're our attempt to overcome the limitations in Foldit.
[2:40 PM] horowsah: @maithra in theory, yes it is going to do what it's going to do in wet lab, but there are things that can be done to influence whether it folds properly or not
[2:41 PM] Susume: @beta_helix I was hoping you could say something about recent ED puzzlses but I guess there is still one open, maybe it's too soon
[2:41 PM] HuubR:In my mind, rubber bands is what you use to get the backbone to the shape you want. Then you use Mutate to fit the AAs that go well with that backbone shape. Does that make any sense at all?
[2:41 PM] Dudit: What is the Priority in Foldit Development & what is the Final Goal in Foldit Development?
[2:41 PM] rmoretti: HuubR - that's a great way of looking at it.
[2:41 PM] ZeroLeak7: is it possible in future, that we can print the proteins with a 3D printer? Bio-printer!
[2:41 PM] HuubR::-) @ZeroLeak7
is it possible in future, that we can print the proteins with a 3D printer? Bio-printer!
[2:41 PM] sethcooper: we've done that in the past!
[2:41 PM] beta_helix: @Dudit The final goal is a Nobel Prize for Foldit players
[2:42 PM] rmoretti: Dudit - There really isn't a final goal in Foldit development -- we want to keep improving it as a platform for biochemistry and structural biology research.
[2:42 PM] maithra: My point is: if you want the protein to fold up in the wet lab then it should be able to fold up without rubber band. That was the test I was trying in reloading the same aa and structure from the previous puzzle.
[2:42 PM] ZeroLeak7: woow
[2:42 PM] ZeroLeak7: Nobel Prize =.O
What is the Priority in Foldit Development & what is the Final Goal in Foldit Development?
[2:42 PM] neilpg628:I don't know if there is a final goal (others might have a different opinion) but I think the priority is to find and solve problems in protein design that human ingenuity is specifically useful for
[2:42 PM] rmoretti: As long as there's unsolved problems citizen scientists can contribute to, we want to make that possible.
What is the Priority in Foldit Development & what is the Final Goal in Foldit Development?
[2:43 PM] sethcooper: one thing we are looking at is making the tutorial more adaptive to how well players do
[2:43 PM] maithra: I would like to know whether the foldit designs you have successfully recreated in the past were able to fold without any help.
[2:43 PM] sethcooper: i think we're also interested in a VR version
[2:43 PM] Susume: rubber bands help it get into the shape you want, then you have to remove rubber bands and get it to stay there and score well
[2:43 PM] milkshakeiii: in terms of science we have several teams working on different goals, but some of the important ones are: binders, symmetry puzzles, electron density
[2:44 PM] jflat06: @maithra - one thing to note is that foldit isn't a physics simulation. Wiggle isn't a physics simulation - it is just an optimization algorithm that is relying on physical and statistical score terms.
[2:44 PM] rmoretti: Maithra - True. A good step is to remove the rubber bands and see if the structure is stable without them. -- And all of the foldit designs which work in the lab have been able to fold without help (or at least without any more help than is normally present in cells.).
rubber bands help it get into the shape you want, then you have to remove rubber bands and get it to stay there and score well
[2:44 PM] ZeroLeak7: yes, but it is not that easy
[2:44 PM] jflat06: So we wouldn't expect it to be able to find shapes alone - it needs things like rubber bands to guide it towards the true shape, with the assistance of a human brain
[2:45 PM] ZeroLeak7: I have try to bend the helices now @Susume
[2:45 PM] Susume: you can get the 3d printer plans for the foldit designs in the PDB from: https://3dprint.nih.gov/
[2:46 PM] brunokestemont: HappyFoldit brirthay all. OK for Player's Nobel price ;)
[2:47 PM] Sciren: Yes indeed happy birthday Foldit!
[2:48 PM] horowsah: I wonder if you can design a protein birthday cake...
[2:48 PM] brunokestemont: In a far future, they will think Foldit is the First name of Players. Foldit will become a commun first name.
brunokestemont: In a far future, they will think Foldit is the First name of Players. Foldit will become a commun first name.
[2:49 PM] beta_helix: https://pubmed.ncbi.nlm.nih.gov/?term=foldit+players
foldit players - Search Results - PubMed
foldit players - Search Results - PubMed

[2:49 PM] milkshakeiii: alpha helixes would be pretty hard to make into a cake xD
[2:50 PM] maithra: Another question: in which part of the cell is the protein folding up in the wet lab? In the cytoplasm or in the nucleus of the cell?
[2:50 PM] Susume: oh sad, pubmed does not find our ED papers under our name
[2:50 PM] rmoretti: People were showing some pretty impressive barrel structures that would probably make a nice cake.
[2:51 PM] alcor29:Alternate layers of bacon and eggs.
[2:52 PM] HuubR:Donut? (hang on for a screenshot...)
maithra: Another question: in which part of the cell is the protein folding up in the wet lab? In the cytoplasm or in the nucleus of the cell?
[2:52 PM] neilpg628: That would be in the cytoplasm
[2:52 PM] rmoretti: @maithra Proteins aren't typically expressed in the nucleus. Proteins are almost always expressed in the cytoplasm, and then moved to the nucleus later. (Also, they're often expressed in E. coli bacteria, which don't have a nucleus at all.)
[2:52 PM] HuubR:IMAGE: http://fold.it/portal/files/chatimg/irc_977284_1620679955.png
[2:52 PM] ZeroLeak7: @HuubR wooow
[2:52 PM] rmoretti: (Moved to the nucleus later if they need to be in the nucleus -- most proteins don't.)
[2:53 PM] Susume: #beta_bagel
[2:53 PM] HuubR:lol, I like that term :-)
[2:53 PM] jflat06: yeah that's great
HuubR:IMAGE: http://fold.it/portal/files/chatimg/irc_977284_1620679955.png
[2:53 PM] Sciren: #beta_bundt_cake

[2:53 PM] horowsah: there we go!
[2:53 PM] donuts554:hello
[2:54 PM] beta_helix: speaking of donuts...
[2:54 PM] ZeroLeak7: donuts554 hello
[2:55 PM] donuts554:Hello how are you?
[2:55 PM] brunokestemont: Donuts by HuubR scores well. i wonder: it is possible in nature ?
[2:55 PM] beta_helix: @everyone Any questions about the 13 years of Foldit?
[2:56 PM] jflat06: we have quite a few foldit historians here
[2:56 PM] brunokestemont: Do you have an ie of the total number of players who at least tried to play som epuzzles ?
[2:56 PM] horowsah: on the question of whether you can make a protein bagel in nature
[2:56 PM] brunokestemont: idea
[2:56 PM] ZeroLeak7: is there a list, how many people worked with Foldit: Developers, Scientist etc.?
[2:57 PM] maithra: Do you have plans to move to/ create a 64 bit version of Foldit? Most PC-s come with 8-16 GB memory nowadays - what cannot be used all by a 32-bit foldit.
[2:57 PM] ZeroLeak7: in Numbers
is there a list, how many people worked with Foldit: Developers, Scientist etc.?
[2:57 PM] josh: https://fold.it/portal/info/credits this?
[2:57 PM] sethcooper: I think it's well over 500K but I haven't checked in a while
@everyone Any questions about the 13 years of Foldit?
[2:57 PM] Dudit: Are there any prediction of when will Foldit out of Beta Version?
[2:57 PM] ZeroLeak7: woooow
[2:57 PM] HuubR:Wow, @Susume :-o
[2:57 PM] ZeroLeak7: thank you seth
Are there any prediction of when will Foldit out of Beta Version?
[2:57 PM] josh: Technically, never. We are a "continuous beta" software
[2:57 PM] ZeroLeak7: good to know
Are there any prediction of when will Foldit out of Beta Version?
[2:58 PM] josh: https://en.wikipedia.org/wiki/Perpetual_beta
Perpetual beta
Perpetual beta is the keeping of software or a system at the beta development stage for an extended or indefinite period of time. It is often used by developers when they continue to release new features that might not be fully tested. Perpetual beta software is not recommended for mission critical machines. However, many operational systems fin...
[2:58 PM] donuts554:What was done on Foldit's first birthday?
[2:59 PM] HuubR:@josh: in other words: it's not a bug, it's a feature
[2:59 PM] MirsadaH:Hi everyone, is there any chance to see Foldit app on Android? If, yes, where is it in store?
[2:59 PM] josh: ;)
MirsadaH:Hi everyone, is there any chance to see Foldit app on Android? If, yes, where is it in store?
[2:59 PM] sethcooper: there is a chance
[2:59 PM] ZeroLeak7: yes android, would be nice!
[3:00 PM] MirsadaH:nice, looking forward to see it soon
[3:00 PM] brunokestemont: I see a new user with number 1030585. Would it be near to the total number of players (counting the mysterious Ashley)?
[3:00 PM] ZeroLeak7: would be awesome mobile folding hehe
[3:01 PM] beta_helix: Doesn't Ashley have more than one account?
[3:01 PM] jflat06: @MirasadaH there's some technical hurdles to releasing on android/iOS, but we're working on some things that could make it easier
[3:01 PM] Susume: Ashley is legion
[3:01 PM] josh: brunokestemont that might be a rough approximation
[3:01 PM] ZeroLeak7: it should run on nvidia shield
[3:02 PM] ZeroLeak7: streaming is the future
[3:02 PM] alcor29: How about fire OS?
[3:03 PM] Dudit: Make Foldit touchscreen friendly
Make Foldit touchscreen friendly
[3:03 PM] sethcooper: Foldit should be touchscreen friendly!
[3:03 PM] MirsadaH:or even compatible with VR hardware/software hehe
[3:04 PM] Formula350: I don't think that number is accurate Bruno. Baker's user ID is something like 2430, and from what I could tell that was the first user.
[3:04 PM] sethcooper: we at one point had a touchscreen version but I'm not sure if it made it's way into the released version

[3:04 PM] donuts554:What do you think is Foldit's most memorable birthday?
[3:04 PM] sethcooper: a few things had multitouch support - pull, move, and camera controls mainly
[3:05 PM] horowsah: well, on the 21st birthday, maybe we'll do a puzzle on alcohol dehydrogenase
[3:06 PM] Formula350: The Android Remote Control app has limited touch capability, as does Foldit in general. It's not the most friendly for input/control, but it IS doable. I think of the Remote Control app as more of a thing to check up on how a recipe is running or start a new one. I don't know if it'd handle actual play very well. (But I hadn't tried, eitehr!)
[3:06 PM] beta_helix: @donuts554 I just looked to see if we did anything for the first Foldit anniversary, but I don't see any posts about it. I only found an email from sethcooper sent to the Foldit team (which was probably only 3 people at the time!)
[3:07 PM] Formula350: Though I'd love to see the Android App (since it's just a Unity-Engine front-end) ported to Desktop, to let us run it as the front-end UI for various clients opened either on the same computer or via network. Allowing us to jump betwixt the clients from a single remote window :}
[3:07 PM] sethcooper: Foldit user id 1 was originally Janos I think
[3:08 PM] jflat06: (since re-written to the Admin account)
[3:09 PM] maithra: A desktop/laptop computer with 4 cores might run 4 different clients with Formula's design idea. I would love that.
donuts554:What do you think is Foldit's most memorable birthday?
[3:09 PM] beta_helix: Probably the 5th anniversary, because katfish made a really cool poster for it... with a timeline of all your accomplishments.
[3:09 PM] Formula350: Janus was the roman deity of doorways. A "Janus Account" would make for a cute nickname for a Admin Account, in that regard haha
[3:10 PM] sethcooper: i think the next that's an actual person is Zoran with 42
Janus was the roman deity of doorways. A "Janus Account" would make for a cute nickname for a Admin Account, in that regard haha
[3:10 PM] Sciren: That's actually super clever!
[3:10 PM] donuts554:Oh ok
[3:11 PM] jflat06: Meanwhile I'm sitting here at 220130
[3:11 PM] SuperNova185: This is a back-in-the-day blog link to FoldIt MacArthur grant appeal: https://www.nanopaprika.eu/profiles/blogs/support-stem-gaming-support
The International NanoScience Community - Nanopaprika.eu
Support STEM Gaming / Support FOLDIT's MacArthur Foundation grant a...
. The Foldit research team (read my earlier post) is striving to extend the Foldit application into a biochemistry tool for grade-schoolers [http://fold.it/portal/] in order to "develop specific technological and social scaffolds to support learning ofmultiple science proficiencies (e.g., interest in science, abstractknowledge, scientific prac...
[3:12 PM] Dudit: Is it possible that Foldit computation runs on the server (to minimize the lag) ?
[3:12 PM] SuperNova185: This is when I was an academic librarian trying to get STEM in the programmes. The powers that be went with STEAM instead.
[3:12 PM] ZeroLeak7: coool
[3:12 PM] Formula350: Maithra that's pretty much what I was envisioning, yes My hope being that with the client minimized and the Remote Control app, that it might not experience the same "slowdowns" while running a recipe since that client could perhaps have its UI stuff offloaded to this Remote Client. However that's also my non-coder-dray-dreaming at play... lol
Probably the 5th anniversary, because katfish made a really cool poster for it... with a timeline of all your accomplishments.
[3:12 PM] beta_helix: sadly I lost the physical copy of the Foldit poster coming back from the Science & Engineering festival in DC... Southwest never found it. I like to think there is someone near the Providence airport with a cool Foldit poster in their room
[3:12 PM] Formula350: hah Thanks Sciren
[3:12 PM] SuperNova185: I interviewed Seth Cooper for my nanogaming blog.
[3:13 PM] jflat06: @Dudit if you pay for it! It's actually not very practical to do that, because we would end up running the computations for an unbounded number of clients.
[3:13 PM] SuperNova185: That was 2010.
[3:13 PM] jflat06: Which would grind our servers to a halt pretty quickly after even a handful of people were connected.
[3:13 PM] ZeroLeak7: I would pay 9,99 $
[3:14 PM] ZeroLeak7: in month
[3:15 PM] SuperNova185: This was when FoldIt was competing for the Digital Media Learning funding grants : hey've entered the Digital Media Learning Competition [http://www.dmlcompetition.net/pligg/story.php?title=849
[3:15 PM] SuperNova185: as contenders for a Learning Design Labs award, underwritten by the MacArthur Foundation.
[3:15 PM] maithra: I thought the servers only pass the scores of other players. The folding happens on the client computer, right? Passing scores cannot be such a demand on the server.
[3:16 PM] Formula350: Yes Maithra. I think Dudit was pitching a request/idea to have a Server-Side version, to perhaps allow for something like a Mobile version, so that your mobile device wouldn't be taxed with the computational workload.
[3:16 PM]
donuts554:Oh ok
[3:16 PM] ZeroLeak7: can we spend money to Foldit?
[3:17 PM] maithra: Our mobile devices have quite a powerful computer in them, I think.
[3:17 PM] SuperNova185: So, can I regain all of my points garnered over more than a decade - lost during hiatus and sabbatical?
[3:17 PM] maithra: Our smartphone can do face recognition - that is AI. I expect it could handle the folding as well.
[3:18 PM] donuts554:How could the protein folding problem be solved?
[3:18 PM] beta_helix: Other games (such as our friends at EteRNA https://eternagame.org/about) do take donations, but you all contribute so much already that we avoided this.
[3:18 PM] ZeroLeak7: exactly, but our computers could handle much more AI too. We need new functions to write AI-RECIPES
[3:19 PM] Formula350: I suspect they'd be capable of folding if it were ported to Android/iOS, in so far as being not much slower than doing it on a PC with a CPU running at a similar frequency (GHz). Though, that comes back to the touch interface and whether that's sufficient enough...
[3:19 PM] jflat06: mobile processors are definitely getting more powerful, but they still have to operate on very small power budgets that keep them from competing with desktop processors
[3:19 PM] maithra: I would rather have a 64-bit version of foldit than a mobile version.
[3:19 PM] brunokestemont: For AI, don't yo need access to huge databanks? I s rebuild or remix a kind of AI?
[3:20 PM] sethcooper: 64 bit does seem pretty reasonable!
[3:20 PM] Formula350: Granted they lack some instruction sets, which Foldit may rely heavily on, so if they're being emulated on ARM that might be problematic.
[3:20 PM] ZeroLeak7: neuronal networks is a big thing @Bruno Kestemont
[3:21 PM] Formula350: We could run AI via OpenCL on our GPU's *cough* lol But that's a WHOLE other bag of worms lol
[3:21 PM] rmoretti: brunokestemont - It depends on the type of AI, but a lot of the newer ones require large datasets in the training phase. Typically you don't need to have access to the databanks for the actual usage, as the info in the datasets are embedded (in a sense) in the model themselves.
[3:21 PM] ZeroLeak7: yeees thats it @Formula350
[3:21 PM] jflat06: Rebuild/Remix aren't AI - rebuild just takes known segments of 3-residues and inserts them to make a new backbone for a region... and then tries to make it reconnect. Remix does spatial hashing to do a lookup for known good backbones that have the correct endpoints to hook up with your two chosen endpoints.
[3:22 PM] ZeroLeak7: we could train the neuronal net with Foldit for a few years
[3:23 PM] ZeroLeak7: some Ideas ^^
[3:23 PM] rmoretti: We are interested in incorporating AI techniques into Foldit, though. trRosetta (the Baker Lab's verison of Alpha Fold) is the obvious first step, but other places we could employ AI to help out players is something that's on our minds. (Many in the Rosetta community are exploring various ways of applying AI to structural modeling tasks.)
[3:23 PM] maithra: foldit users can generate many false solutions so far. AI needs positive examples too. I mean examples that are folding up in the wet lab properly.
[3:25 PM] maithra: I think that the 32 bit version of foldit is not up to AI tasks. You need 64 bit foldit for that.
[3:25 PM] Formula350: We need a new tool: "Re-re-re-REMIIXX *airhorn sound*" which lets Rebuild run until it finds a suitible pose, and then Remix finish it off by inserting valid ("known good backbone") poses. If the Remix portion is unable to, then it tries again with a new Rebuild->Remix. Might allow for Remix to work on sections >9seg like Rebuild can, if it broke up the size into digestible chunks.
[3:25 PM] ZeroLeak7: yes that's not easy, but we can sort out the false solutions
[3:25 PM] ZeroLeak7: yes we need 64 bit a lot of ram for AI
[3:25 PM] pc: hi
[3:25 PM] pc: happy birthday ^^
[3:26 PM] beta_helix: @pc Hello, welcome to the party!
[3:26 PM] ZeroLeak7: A 64-bit register can theoretically reference 18,446,744,073,709,551,616 bytes, or 17,179,869,184 gigabytes (16 exabytes) of memory. This is several million times more than an average workstation would need to access
[3:27 PM] ZeroLeak7: soon we have exascale supercomputers in 20 years hehe
[3:27 PM] jeff101: Happy Birthday to Foldit! I'm glad to see experiments are running in the lab again.
[3:28 PM] beta_helix: Any final questions?
[3:28 PM] Formula350: I might be wrong but I think the benefit in Foldit's context would be that 64bit registers could allow faster transfer of data vs 32bit... but I'm venturing outside my area of even *partially* knowing what I'm talking about lol
[3:28 PM] beta_helix: @jeff101 so are we
[3:28 PM] ZeroLeak7: hmm ok so it will be
[3:28 PM] Formula350: Is the Cake also a lie in Foldit?
[3:28 PM] HuubR:?
[3:28 PM] alcor29:What do you all see for this coming year?
[3:29 PM] ZeroLeak7: fun
[3:29 PM] maithra: 64 bit computer programs can use more memory than 32 bit computers - that is the big difference.
Is the Cake also a lie in Foldit?
[3:29 PM] Sciren: The cake is always a lie, you should never trust it.(edited)
[3:29 PM] ZeroLeak7: have fun
[3:29 PM] pc: is David Baker connected to the chat ?
[3:29 PM] jflat06: except it wasn't a lie in the end!
[3:29 PM] Formula350: (That's a Portal game reference for anyone not familiar, just google "The cake is a lie")
[3:29 PM] HuubR:Thx
[3:29 PM] ZeroLeak7: Living you Life Guys and Girls
[3:30 PM] beta_helix: @alcor29 I see exciting Electron Density results and improvements
[3:30 PM] ZeroLeak7: cya
[3:30 PM] Formula350: Cya Zero
[3:30 PM] Formula350: Do we see a new website coming online? glances at jflat
[3:30 PM] horowsah: goodbye all, i look forward to protein cake!
[3:30 PM] sethcooper: bye everyone! thanks!

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office hour 5/26/21- led by milkshakeiii

4:00 PM] milkshakeiii: Hello! I am a programmer at the IPD where Foldit was originally created, and my office hours is starting now. I can talk about the technical side of Foldit.
[4:00 PM] milkshakeiii: Alternatively, I can talk about why Illinois is the best state in the USA
[4:01 PM] milkshakeiii: (Because corn is delicious, duh)
[4:03 PM] Susume: lol hi milkshake!
[4:04 PM] Susume: I'm only here for a couple minutes, but could you talk a bit about how trRosetta is going to be exposed in foldit?
[4:04 PM] jmbrownlee333: Escape to Wisconsin
[4:04 PM] milkshakeiii: I could talk about that, however I think you are the expert on it!
[4:05 PM] milkshakeiii: I believe we are thinking about trying to make it a simple metric at first
[4:05 PM] Susume: the part I know nothing about is the user interface
[4:05 PM] milkshakeiii: Probably a simple objective would be the first step
[4:05 PM] milkshakeiii: Then maybe another window like the blueprint window with information
[4:06 PM] Susume: ok cool! I gotta run, have fun yall!
[4:06 PM] milkshakeiii: Ok see ya!
[4:12 PM] pc: hi
[4:13 PM] milkshakeiii: o/
[4:16 PM] pc: are new lua functions will be added in foldit ?
[4:17 PM] pc: I waited somes like "detect core in a protein" or add a black / white list in mutate.
[4:17 PM] pc: custom mutate in recipes are very slow
[4:18 PM] pc: but of course it can be good if we can add some white list as a player too.
[4:18 PM] pc: and for each segment (not only a global white list)
[4:19 PM] milkshakeiii: we have recently added the ability to retrieve information from filters in lua scripts
[4:19 PM] milkshakeiii: detect core in a protein sounds like something that could be done using that interface
[4:19 PM] milkshakeiii: using the core existence filter
[4:19 PM] pc: ah cool. idealy it is better if thoses fonctionscan be called without filter in the puzzle.
[4:20 PM] milkshakeiii: yeah that would be good. at least core existence filter is pretty common tho I think
[4:20 PM] milkshakeiii: white listing residues during mutate also sounds like a good idea
[4:21 PM] milkshakeiii: i think you can sort of do that using selections?
[4:21 PM] pc: when I create a base protein in design puzzle, when I mutate I have often serine in core.
[4:21 PM] pc: there is some tips to avoid that, but it is better if the first mutate give good AA at begin ^^
[4:22 PM] pc: I can use core existence with the new lua fonctions so, it is good ^^
[4:24 PM] milkshakeiii: I see, yeah
[4:24 PM] pc: creating a first protein is not easy. maybe we will need later a new tool to construct them (and not only tripple helix)
[4:25 PM] milkshakeiii: maybe hallucination using trRosetta
[4:25 PM] pc: I often create tripple helix because I have a lot of difficulty to keep a correct sheet in my protein
[4:27 PM] milkshakeiii: from what I understand, protein scientists at the IPD do the same thing, so, you're not alone
[4:27 PM] milkshakeiii: also even nature makes a lot of triple helixes i think
[4:27 PM] milkshakeiii: i'm not the expert on protein science tho so take what I say with a grain of salt
[4:28 PM] pc: Yes. Maybe it can be usefull to try some differents shapes, because some design puzzles can have no very good solutions with a tripple helix.
[4:28 PM] milkshakeiii: yeah diverse backbones are more exciting and interesting
[4:29 PM] pc: I saw Mers puzzle results. Maybe we needed bigger contact surface area (sorry it is a scientific question ^^)
[4:29 PM] pc: players need to know "what to do now" after something didnt work.
[4:30 PM] pc: or "is there a new tool to test something else?"
[4:30 PM] milkshakeiii: yeah, I know bkoep is working on that
[4:30 PM] pc: are some of our solutions tested in a physic simultor to know why it didnt work in lab ?
[4:31 PM] milkshakeiii: usually they aren't tested in the lab unless they look good from the simulation standpoint
[4:31 PM] pc: It can be very intresting for player to see that too. I already saw for a protein fold in 3d from rosetta. it was cool ^^
[4:32 PM] pc: Can be interesting to see when it comes off and why
[4:34 PM] pc:
https://www.youtube.com/watch?v=gFcp2Xpd29I : like this but for design puzzles
Pande Lab Science
Simulation of millisecond protein folding: NTL9 (from Folding@home)

[4:35 PM] milkshakeiii: oh, interesting
[4:35 PM] milkshakeiii: also, also sprach zarathustra as the background music ha
[4:38 PM] alcor29: Hi milkshake. What about this dream scenario. We are given x number of residues. Then in a sort of blueprint tool we specify I want y number of helices, sheets, and ferrodoxing fold with proper chirality? It would save us a lot of 'menial' uncecessary work.
[4:39 PM] pc: yea like a super tool that create the first structure ^^
[4:39 PM] milkshakeiii: yeah the blueprint tool now is quite clunky
[4:39 PM] milkshakeiii: just today in a meeting somebody mentioned redoing it
[4:40 PM] milkshakeiii: it needs some iteration
[4:40 PM] HuubR: I often use the Blueprint window just as a tool to quickly select a number of residues.
[4:40 PM] pc: blueprint tool still usefull in midgame sometimes
[4:41 PM] milkshakeiii: yeah it's useful for sure, could be even more so
[4:42 PM] pc: but yes, when a loop become not ideal, it is very hard to fix. remix doesnt work most of the time. blueprint make too much moves.(edited)
[4:43 PM] HuubR: What if we could copy and paste the backbone shape from one part of the Blueprint window to another?
[4:45 PM] pc: I imagine this : A super creator tool, in a "protein creation mode" at start that have no editable residues. Only Helix, loops and sheets that we can move or turn. and when it is ok, we can convert it to regular foldit protein.(edited)
[4:46 PM] pc: and of course create 310 helix
[4:47 PM] pc: There is 2 kinds of Helix if I understand
[4:47 PM] pc: https://en.wikipedia.org/wiki/310_helix
310 helix
A 310 helix is a type of secondary structure found in proteins and polypeptides. Of the numerous protein secondary structures present, the 310-helix is the fourth most common type observed; following α-helices, β-sheets and reverse turns. 310-helices constitute nearly 10–15% of all helices in protein secondary structures, and are typically obser...

[4:47 PM] milkshakeiii: that would be quite great
[4:48 PM] alcor29: What area are you working on currently milkshake?
[4:48 PM] pc: 310 helix are maybe better for symetric puzzles
[4:48 PM] milkshakeiii: i'm currently working on improving the integration between Foldit and rosetta
[4:49 PM] milkshakeiii: Foldit is currently using a modified version of rosetta from 6 years ago, with some parts from 13 years ago
[4:49 PM] milkshakeiii: we want to be able to easily plug in new versions of rosetta as they come along
[4:49 PM] milkshakeiii: so I'm working on that
[4:50 PM] alcor29: So it's a conversion project but not necessarily increasing our design capacities?
[4:50 PM] milkshakeiii: yes, but the new versions of rosetta are needed for a lot of design stuff
[4:50 PM] pc: we will have new "score parts" in this new version of rosetta ?
[4:50 PM] milkshakeiii: such as introducing new calculations or trRosetta
[4:50 PM] milkshakeiii: I think there have been some minor changes in score parts in the last 6 years, yes
[4:51 PM] milkshakeiii: however, the core score function hasn't changed much
[4:51 PM] milkshakeiii: objectives/filters have, though
[4:52 PM] pc: And maybe some score parts will replace some objectives. Mutate function often doesn't take count about objectives (like BUNS)
[4:54 PM] milkshakeiii: yeah the interaction between mutate and objectives is another important question
[4:54 PM] pc: thanks ^^
[4:54 PM] cjddig: Are there the thing you're planning to make/release shortly?
[4:55 PM] milkshakeiii: well, dojo mode just got released!
[4:56 PM] milkshakeiii: yesterday!
[4:56 PM] milkshakeiii: and there is another thing coming up which I'm not sure if it has been announced yet
[4:57 PM] milkshakeiii: it hasn't been, secret secret 8)
[4:57 PM] cjddig: I'm enjoying dojo, but I think there're some technical issues about it.
[4:58 PM] milkshakeiii: yeah there are
[4:58 PM] milkshakeiii: like slow load times between levels
[4:58 PM] milkshakeiii: Josh is hard at work on that
[5:00 PM] pc: most of dojo puzzles are solve with wiggle
[5:00 PM] milkshakeiii: i think once you solve a few easy ones liek that it should start giving you hard ones though
[5:00 PM] cjddig: I think not that many people play dojo now, but it is the fact that it's funny mode. Now I cannot solve most levels I meet!
[5:01 PM] milkshakeiii: yeah Josh needs more data so he can create a range of difficulties as opposed to jsut wiggle/unsolveable
[5:01 PM] milkshakeiii:
so play it more and Josh will have more data ^_^
[5:02 PM] alcor29: Thanks milkshakeiii.
[5:02 PM] milkshakeiii: thanks all! the office hours is technically over now but I'm still around for a bit 8)
[5:02 PM] pc: thanks ^^
[5:03 PM] cjddig: Thanks!
[5:03 PM] pc: thanks for answers.
[5:04 PM] milkshakeiii: Thanks for questions 8)
[5:05 PM] cjddig: I had breakfast in the middle of Office Hour... I couldn't be here.
[5:06 PM] milkshakeiii: the most important meal of the day
[5:08 PM] pc: it is 1:00h in france ^^
[5:09 PM] milkshakeiii: yikes ha
[5:10 PM] alcor29: Do you have an idea when the conversion will be done?
[5:11 PM] milkshakeiii: the first pass will be done next month probably but then there are many more steps after that
[5:12 PM] alcor29: Ah. Tx.
[5:12 PM] alcor29: And I'm sure there will always have to be maintenance.
[5:14 PM] milkshakeiii: there's always that, ha, hopefully this will actually help reduce maintenance though
[5:17 PM] milkshakeiii: i'm off, good luck all!

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
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Groups: Foldit Staff
Office hour 6/10/21- led by beta_helix and sethcooper

2:00 PM] beta_helix: Yes it does! Seth and I will start it soon
[2:02 PM] beta_helix: Hi everyone, and welcome to Foldit Office hours! Seth Cooper and I will be here for the next hour to answer any questions.
[2:03 PM] beta_helix: We're also happy to talk about the new C++ developer job ad that we posted: https://fold.it/portal/node/2011713
Foldit is hiring: C++ developer focused on Electron Density
Foldit is hiring: C++ developer focused on Electron Density
[2:03 PM] sethcooper: hello!
[2:03 PM] spvincent:hello!
[2:03 PM] jeff101:hi
[2:04 PM] beta_helix: Hi everyone
[2:04 PM] HuubR:Hi from Europe as well :-)
[2:04 PM] beta_helix: I hope it's not too late
[2:04 PM] spvincent:I was wondering about the binder design puzzles: they seem a bit of a disappointment.
[2:05 PM] BletchleyPark: good evening
[2:05 PM] spvincent:How different are the computer-designed solutions that showed some binding in the last mers puzzle.
[2:05 PM] beta_helix: As my thesis advisor used to tell me when I was getting frustrated: "It was an easy problem, it would have already been solved."
[2:05 PM] beta_helix: Hi BP!
[2:05 PM] BletchleyPark: made it o this one :)
[2:05 PM] spvincent::-)
[2:06 PM] beta_helix: Yay!
[2:06 PM] beta_helix: I will be honest and say that Seth and I are not the binder design specialists, so we don't know much more than the blogpost about it: https://fold.it/portal/node/2011554
Experiment results for MERS-CoV binders
Experiment results for MERS-CoV binders
[2:06 PM] jeff101:what did you propose in the NSF / cryo-EM grant that was funded?
[2:06 PM] beta_helix: However, I tend to think about it in terms of where Foldit design was 10 years ago.
[2:07 PM] beta_helix: Seth, remember how it seemed like a bit of a disappointment at the time?
[2:08 PM] sethcooper: well, there was certainly some work to do to get to working designs!
[2:08 PM] spvincent:Perhaps we could have have one of the partially successful designs as a starting point 8in a future puzzle.
[2:09 PM] beta_helix: Exactly. It was really rough for a while. Think back to the early symmetry puzzles where the top scoring solutions looked really cool (like a pillow, for example) but would never fold in nature. We had to fix the score function significantly to get to the 2019 results.
[2:09 PM] jeff101:what can you tell us about Foldit developments coming soon? what are you working on?
[2:09 PM] beta_helix: (and when I say "we", I mean bkoep )
[2:10 PM] sethcooper: i have been working on a 64-bit windows build
[2:11 PM] jeff101:that's good. folks have been requesting that.
[2:11 PM] BletchleyPark: That shouls allow for larger designs
[2:11 PM] sethcooper: i'd say its pretty much working at this point(edited)
[2:11 PM] sethcooper: i may have fixed audio for Linux in the process (I think I heard that didn't work for some people)
[2:12 PM] BletchleyPark: I notice that keyboard commands get lost in the client
[2:12 PM] BletchleyPark: has this been tracked down as well ?
[2:12 PM] BletchleyPark: (and congrats for getting the 64 bit build working)
[2:12 PM] sethcooper: that i'm not sure about
[2:12 PM] jeff101:are folks doing experiments in the lab again?
[2:14 PM] beta_helix: @jeff101 w.r.t the funded NSF grant, it's basically tackling 2 new components:
[2:14 PM] beta_helix: • Integrating new crystallography refinement capabilities within Foldit. • Adding new modes that allow much larger proteins to be handled in Foldit for cryo-EM.
[2:15 PM] HuubR:Sounds interesting, but please tell us a bit more :-)
[2:15 PM] beta_helix: The general idea is to make Electron Density puzzles a lot easier for you... I know jeff101 has suggested many cool ED features, for example
[2:16 PM] jmbrownlee333: I wish ED puzzles handled discontinuous fragments better. not scoring -99999
[2:17 PM] beta_helix: So one goal (specifically for large cryo-EM structures) is to implement a new Foldit mode where rather than all residues being scored, only the subset being worked on by the user at that time would be used.
[2:17 PM] jmbrownlee333: also wish we had poly ala capabilities.
[2:17 PM] jeff101:are one-way bands on your list of features to implement?
[2:18 PM] BletchleyPark: Would the 64-bit version also allow for more AI assistance in the client for design choices ?
[2:18 PM] beta_helix:
The remainder of the protein will have its energy cached before being recombined.
[2:18 PM] jmbrownlee333:nice. yhat will help a lot
[2:18 PM] beta_helix: @jmbrownlee333 yeah, hopefully that will address your concern!
[2:19 PM] sethcooper: it might potentially if the AI needs more memory, so that's a possibility
[2:19 PM] HuubR:So how do you define the subset that is being worked on?
[2:20 PM] BletchleyPark: Could there be a way for clients to communicate with eachother, either through a disk file (Share mode) or otherwise ?
[2:20 PM] BletchleyPark: as in: exchange paramters, results etc
[2:21 PM] sethcooper: maybe, what would the use case for that be?
[2:21 PM] BletchleyPark: I find loading and saving solution files very slow lately, something faster than that would be welcome
[2:21 PM] HuubR:BP, you mean parallel computing?
[2:21 PM] beta_helix: @HuubR You would essentially use cutpoints, but you can imagine this being particularly useful with much bigger density clouds... if we don't know where a monomer fits in a huge density that fits multiple domains, for example.(edited)
[2:22 PM] BletchleyPark: I run several clients, looking for a good pose, if one of them find one, it could communicate it to the other ones, yielding a new startpoint
[2:22 PM] BletchleyPark: @HuubR, essentially yes
[2:22 PM] beta_helix: @jeff101 once we hire someone dedicated to working on this, we plan to go through the long list of ED features that we've wanted to implement over the many years (edited)
[2:23 PM] jeff101:how long can the position last?
[2:23 PM] sethcooper: i see
[2:23 PM] Susume (she/her): so like that giant virus donut, where there were lots of copies, we might have half the protein in density copy A and the other half in density copy B
[2:23 PM] beta_helix: The grant is 3 years.
[2:23 PM] beta_helix: Exactly, Susume.
[2:23 PM] sethcooper: i'm not sure if the file system itself would be the slowest part of loading a solution
[2:24 PM] BletchleyPark: I use SSDs and the clients used to be quicker in loading
[2:25 PM] beta_helix: Or you can imagine there is a big cryo-EM complex with thousands of residues, and we just want to tackle one 300-residue domain in there... but we don't know where it fits. With this feature we could give you that 300-residue chain and you would be able to try all the different places where it could fit (without completely killing your CPU!)(edited)
[2:26 PM] sethcooper: i wonder if the protein size / filters might be part of it as well
[2:26 PM] BletchleyPark: Are the filters enabled while loading ? You might switch that off automatically while constructing the model as it loads
[2:27 PM] BletchleyPark: same for saving
[2:28 PM] sethcooper: i think if the filters are on they get run when loading so the protein can be scored
[2:28 PM] Susume (she/her): @beta_helix do you have any preliminry results from recent ED puzzles?
[2:33 PM] BletchleyPark: test
[2:34 PM] beta_helix: @Susume (she/her) I wanted to look up the correct details, because I know they gave us another target that we will be posting soon. For the 2 previous cases they were able to build the structure by comparing to previous vWa domain crystal structures.
[2:35 PM] Susume (she/her): sry what is vWa?
[2:36 PM] beta_helix: We are fortunate that this lab has many more datasets that they can share with us. Which I think will be good practice for ED puzzles.
[2:37 PM] beta_helix: (Sorry: vWa = von Willebrand factor type A)
[2:37 PM] HuubR:blood clotting?
[2:40 PM] beta_helix: These were the TNK1 puzzles (those proteins are implicated in the regulation of cell growth and cell death).
[2:41 PM] beta_helix: It will be very helpful to have a set of unsolved ED puzzles that we can run, especially when the new tools start being implemented.
[2:42 PM] Nicm25:i didn't know that we was challenging ED of thousands residues. we can it be posted as design puzzle? (and with known AA sequences) was it too early?
[2:42 PM] jmbrownlee333:Do many of them have crystallization domains, as the last one seemed to.
[2:43 PM] beta_helix: @Nicm25 we haven't been able to post any ED puzzles with more than 280 residues, so that was one main goal of this NSF grant. So if anyone knows any C++ experts who would be interested in improving Foldit Let us know! They don't have to be Foldit players
[2:44 PM] beta_helix: @jmbrownlee333 yes indeed
[2:44 PM] beta_helix: How difficult have the recent ED puzzles been?
[2:45 PM] beta_helix: Has the "radius" slider been useful, for example?
[2:45 PM] equilibria: I would say they have been hard, mostly because I could not tell where I was, as in the depth perception was terrible because of the monochrome background
[2:45 PM] jeff101:The sweet spot for the "radius" slider seemed too small. It would be good to have better resolution there.
[2:46 PM] equilibria:Also if i could chop up the electron density data so I could look at one section that would be great
[2:46 PM] jmbrownlee333:The last one was difficult for me because the dinsity seemed uneven. Some areas maddeningly bad. Other people seemed to deal with it better than me.
[2:46 PM] equilibria:^
[2:46 PM] jeff101:It moved from showing too little of the density to showing too much of the density.
[2:46 PM] HuubR:I think the big one (1964) was the third ED puzzle I played, so I was glad we had 2 weeks. Yes, I finally figured out how to make good use of the Radius slider.
[2:48 PM] jmbrownlee333:Better than no slider for sure!
[2:49 PM] beta_helix: Thank you, this is very helpful. It seems like the granularity on the slider could be improved. @equilibria being able to manipulate the ED cloud better is a major goal of the grant.
[2:49 PM] Susume (she/her): in the donut virus, radius took away the flat sides I was using to stay oriented, so I never used it. for others I used it sometiems
[2:49 PM] HuubR:The main point with this Radius was actually figuring out how the pivot point for the "camera" actually works. Up to then I used a sort of trial and error, but with 1964 I think I figured out how to use it properly.
[2:49 PM] jeff101:It would be nice if the Center/Align Protein on Density button would treat the protein like a rigid body and rotate and translate it to get a good fit to the ED/EM.
[2:50 PM] equilibria:I still havent figured out the radius works
[2:50 PM] beta_helix: I know many people have requested the ability to manually erase density (like the eraser tool in paint, but in 3D)(edited)
[2:51 PM] HuubR:@Susume (she/her): I made "flat sides" by folding the (reset) protein into an x, z, and y axis (x along the bottom, y along the top)
[2:51 PM] jeff101:It just has to vary 3 euler angles for rotation and 3 x y z variables for translation. The Nelder Meade SImplex Direct Search method could probably do it.
[2:51 PM] equilibria:wait i understood exactly 0% of that
[2:51 PM] equilibria:can you explain please?
[2:52 PM] jeff101:but you'd have to code it as part of FOldit, not as a recipe, because recipes don't have access to the ED vs x,y,z coordinates data.
[2:53 PM] jmbrownlee333:Wait, there's math involved in this. Wink. Wonderfully wonky Jeff101.
[2:54 PM] BletchleyPark: Would be useful to programmatically alter the rotation axis for a given residu
[2:54 PM] Susume (she/her): a little xyz graphic in the corner like you see in blender or other viewers would make keeping track of up/down etc easier
[2:54 PM] HuubR:https://fold.it/portal/files/chatimg/irc_977284_1615135836.png

[2:55 PM] beta_helix: There used to be a program called ProteinShop when I was in grad school, and it had 3 dials that you could manually move to rotate in the x/y/z planes.
[2:55 PM] Susume (she/her): huubr i see it's square, but it won;t be there when I am folding...?
[2:55 PM] sethcooper: i think it would be pretty straightforward to add axes
[2:56 PM] beta_helix: ...but only for 64-bit windows
[2:56 PM] Susume (she/her): mouse is fine for rotating, what I want is a visual reminder of where up is
[2:56 PM] HuubR:Correct, I only used it while annotating the cloud
[2:56 PM] beta_helix: Got it, just the little arrows.
[2:57 PM] Susume (she/her): more dot colors would be nice too, I have started using double red, red-green, red-purple pairs etc to mean different things
[2:57 PM] HuubR::-)
[2:57 PM] beta_helix: That should be simple to add as well!
[2:57 PM] jeff101:how about orthographic instead of perspective. sometimes I want to align things from front to back, but perspective makes far away things appear closer on the screen than nearby things. Having orthographic would let far away things and nearby things be displayed with the same scale.
[2:57 PM] jmbrownlee333:I hate having one color be the default.
[2:58 PM] jmbrownlee333:for dots
[2:58 PM] HuubR:Oh yes: a setting "use last colour again"
[2:58 PM] jmbrownlee333:: )
[2:59 PM] sethcooper: i think there is an orthographic view already
[2:59 PM] sethcooper: it might be in the advanced view options
[2:59 PM] jeff101:please show me where the orthographic view is
[2:59 PM] beta_helix:Are there any last questions? Thank you all for coming!
[3:00 PM] jeff101:thank you for coming
[3:00 PM] equilibria:thanks for hosting!
[3:00 PM] Susume (she/her): thank you!
[3:01 PM] jmbrownlee333:I just want to upvote Jeff's complaint. "Center on density is worthless as is.
[3:01 PM] HuubR:Thank you, @sethcooper and @beta_helix, for an interesting hour!
[3:01 PM] beta_helix: @jmbrownlee333 thanks... I will double-vote that one
[3:01 PM] jmbrownlee333:Ya thanx guys
[3:01 PM] jeff101:Somewhere I wrote a feedback about how to use Nelder-Meade to fix the center on density tool.
[3:02 PM] BletchleyPark: rhank you
[3:02 PM] equilibria:nelder meade?
[3:02 PM] BletchleyPark: afk
[3:02 PM] equilibria:is that like a separate program?
[3:02 PM] jeff101:In matlab, it is implemented as the function fminsearch. It optimizes without using derivatives.
[3:03 PM] sethcooper: yes thanks everyone!
[3:03 PM] equilibria:what's matlab?
[3:03 PM] beta_helix: Thanks jeff101... I hope we'll hire someone soon to work on these suggestions!
[3:03 PM] sethcooper: i'm looking for the orthographic view option...
[3:03 PM] beta_helix: MATLAB is a program
[3:04 PM] HuubR:https://mathworks.com/
MathWorks - Makers of MATLAB and Simulink
MathWorks develops, sells, and supports MATLAB and Simulink products.
[3:04 PM] jeff101:Nelder and Meade apparently popularized it. It uses simplexes (triangles in 2-dimensions, tetrahedrons in 3-dimensions) and moves their vertices to find the best value of a function in multiple dimensions.
[3:04 PM] jeff101:THe dimensions could be angles, distances, band-strengths, etc.
[3:04 PM] beta_helix: FYI: Most schools have a free version of MATLAB.
[3:05 PM] beta_helix: Thanks again everyone... keep up the great folding!

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office hour 6/23/21- led by Horowsah

[3:00 PM] horowsah: Hi all- I’m here for my office hour. If you don’t remember, I’m a general biochemist (mostly experimental, actually), and I’m mostly involved in ED and educational puzzles with Foldit, but I’m also good for answering general biochemistry questions. I’m not a protein design specialist, though.
[3:00 PM] donuts554:hello
[3:00 PM] horowsah: most of my work is on how nucleic acids affect protein folding, so that covers a lot of biochem
[3:02 PM] jeff101: thanks for coming
[3:02 PM] horowsah: no prob
[3:03 PM] Susume (she/her): I'll pose a non-foldit question then, can you tell ions apart in ED data? there are two xray structs in the PDB of the same protein with an ion visible in the ED, one team identified it as Cl-, the other identified it as Ca2+ (both were present)
[3:03 PM] horowsah: great question
[3:03 PM] jmbrownlee333:nucleic acids affect protein folding, and somehow i think of it the other way, that proteins affect nucleic acid folding. two -way street i guess
[3:03 PM] Susume (she/her): the sidechains were threonine, so I vote for Cl- (ca2+ likes oxygens)
[3:03 PM] horowsah: susume- i published a paper on that recently: https://journals.iucr.org/d/issues/2019/12/00/wa5123/
Acta Crystallographica Section D
Identifying dynamic, partially occupied residues using anomalous sc...
Structural studies of partially occupied, heterogeneous protein systems using crystallography are difficult. Here, methods are presented for detecting these states in crystals.

[3:04 PM] horowsah: short answer- it depends on the ion and the wavelength you use for crystallography. It's really easy to screw it up if you don't do the experiment just right (I've definitely done it before).
[3:05 PM] horowsah: jmbronlee: it is a two-way street. most people think of it the other way around than i do
[3:06 PM] alcor29:Is the massive presence of water fully accounted for or compensated for in any method of analysis or prediction?
[3:06 PM] Susume (she/her): I'll look at paper, ty
[3:07 PM] horowsah: alcor: water is a bugaboo of computational methods for sure. there are lots of models for it that people use, and none are perfect. it's one of the bigger limitations in computational biochemistry. but, it's still improving, and we can do a lot of things with the water models we have now
[3:07 PM] horowsah: in foldit, we use an implicit water model, which works fine for some things and is much faster than an explicit model where you would see all the individual water molecules surrounding the protein (would be awful hard to look at that way too)
[3:09 PM] donuts554:Can orange hydrophobic amino acids be exposed in proteins in water?
[3:10 PM] horowsah: so the dogma is that hydrophobics are buried away from water, but most proteins in nature aren't totally perfect, and there can be a stray hydrophobic here and there that is left on the surface. sometimes that will help in ligand binding
[3:11 PM] jmbrownlee333:Can u give any insight into the quality of ED data we are given . Sometimes they seem to be really crude (crappy phases? ) and other times better. I have similar questions around cryoEM but i don't understand those experiments as well. And what are the hopes for foldit players in the future.
[3:13 PM] horowsah: sure- ED data varies greatly in real life. sometimes it's awesome and high resolution and things are easier, and sometimes it's not. we still need to figure out how to fit it, even if it's not great data. however, that leads to a higher chance of it getting screwed up, which definitely happens. for crystallography, the quality of the data is mostly dictated by how perfectly the protein crystallizes. usually there are imperfections in the crystal that leads to them diffracting worse and giving worse data
[3:14 PM] horowsah: for cryo-em, it's a different set of factors, since you're not crystallizing a protein, but it also has to do with imperfections in the sample usually. for cryo-em, the technology is improving so rapidly that what was considered a great set of data 10 years ago is now thought of by crappy by today's standards.
[3:14 PM] jeff101: are there empty spaces inside the crystal between individual proteins?
[3:15 PM] horowsah: so there are spots where the proteins touch to form the crystal (called crystal contacts), and then there are open spaces as well that are filled with water inside the crystal, and are referred to as water channels
[3:15 PM] jmbrownlee333:Ya but somrtimes I think its the phasing not the diffraction holding us back.
[3:16 PM] horowsah: you can actually use those water channels to soak in things that bind to the protein
[3:17 PM] horowsah: for the phasing- yes, that's still an issue, but less often than it used to be, and as structure prediction improves, it will become less of a problem. That paper I sent in response to Susume's question earlier actually describes a crystallography beamline designed to phase with sulfur in cysteines, which will make it much easier to phase harder crystals.
[3:17 PM] jeff101: do the waters inside the crystal move around? do they show up in the ED data?
[3:18 PM] HuubR: To "soak in things" you would need pretty small molecules, not much bigger than water, right?
[3:19 PM] horowsah: the water does move if you collect the data above freezing, which sometimes is done, but sometimes we freeze crystals to help with diffraction (movement is tough). but we don't see the bulk water that's moving, only water that's in the same spot all the way through the crystal because it's bound to protein.
[3:19 PM] jmbrownlee333:Nice. we don't need no stinking selenoMet.
[3:19 PM] horowsah: For soaking, usually it's small stuff, but occasionally people will soak in things as big as whole peptides
[3:20 PM] alcor29:Can you make a comparison or analogy to 4K vs 8K in visual resolutions?
[3:21 PM] horowsah: hmm, i think so, but we almost never get to 4K quality.
[3:21 PM] horowsah: I'd say usually we're in VHS range
[3:22 PM] horowsah: ...or worse, not sure what that would be
[3:22 PM] alcor29: What limits it from becoming better?
[3:23 PM] horowsah: sometimes it's inherent to the crystal form, sometimes it's limited by extra stuff getting stuck in the crystal. usually, crystallographers don't try to perfect the crystals, just get them to "good enough" which enables a model to be built at all. getting to perfection on the crystal could take decades or would never happen.
[3:24 PM] donuts554:Can Cryogenic Electron Microscopy be used to find the atomic structure of radioactive minerals?
[3:25 PM] alcor29: Going back to jmbs earlier question: " And what are the hopes for foldit players in the future."
[3:25 PM] horowsah: hmm, not positive on that one, and probably not yet; usually minerals are handled by crystallography since they usually are crystalline in pattern when pure
[3:25 PM] horowsah: ah- hopes
[3:26 PM] horowsah: well, we should be starting to introduce new ED features over the next few years that could vastly improve how much control Foldit players have in the process
[3:26 PM] horowsah: we'll want to see how much they help
[3:27 PM] jeff101: Foldit was awarded an NSF grant recently to improve its ED/EM abilities. The grant includes money to hire a programmer and encourages applicants who live near Seattle, Denver, or Boston. Will you be working with the programmer to improve Foldit?
[3:27 PM] horowsah: one of those features in particular will hopefully let foldit players improve the ED as part of the process. I should say this is a long way off.
[3:27 PM] horowsah: Yep, this is one of the tasks that the new programmer will be working on
[3:33 PM] jeff101: What can we expect in upcoming Foldit puzzles?
[3:34 PM] horowsah: hmm, good question. I actually can't mostly remember. I've been thinking mostly about the recent run of ED puzzles, and we likely will continue to have a few more coming up. Not sure on the protein design side.
[3:35 PM] jeff101: Can you tell how we've been doing on recent puzzles? How is our work helping science?
[3:36 PM] horowsah: I can give a pseudo update on the ED puzzles. We'll probably put together a blog post on this at some point, but not sure when. The short answer is, y'all have done really well on those. In some of these cases, it's outdoing scientists' work, in other cases, taking tough ED maps and managing to make them work when the scientists was having a tough time finding their way into it.
[3:36 PM] jmbrownlee333:Why are foldit players expected to be a good contribution to structure solving, compared to professionals and software and AI? I mean this question with respect, biut it feels like reinvention of the wheel, in some respects.
[3:38 PM] horowsah: For structure solving- software still is pretty bad, and nobody's made an AI to do it yet (not sure if and/or when that might happen and how it will do). The basic skills for putting stuff in ED that scientists develop is the same skill Foldit players develop. Except that a lot of scientists aren't very good at it. I'm actually maximally so-so at it. It's because I have terrible visual-spatial reasoning skills. So despite my good scientific thought processes, putting proteins in electron density is something I find very hard, and have spent years becoming merely passable at it as a result.
[3:41 PM] jmbrownlee333:So its a "more hands on deck" kinda thing?
[3:41 PM] jeff101: like 100 heads are better than one?
[3:42 PM] horowsah: in part, but it's also that Foldit players are likely just flat out better at it than a lot of scientists due to good visual spatial skills
[3:43 PM] jmbrownlee333:But sometimes I wish i could see what autobuild would do with the density.
[3:43 PM] horowsah: ah- so in the two ED papers we've published, we do compare to autobuild. Of all of the things we've tried, one kinda worked ok
[3:43 PM] jmbrownlee333:Ok, I like that answer. some people around here have awesome spatial recognition
[3:43 PM] jeff101: is it like in that movie "SLing Blade" where several guys are puzzled why a lawn mower isn't working. Then Billy Bob Thorton's character comes out, looks at it, and says "there's no gas in it" ?
[3:44 PM] horowsah: i've actually never seen sling blade, always wanted to
[3:44 PM] jmbrownlee333:touche
[3:44 PM] Susume (she/her): slingfold
[3:46 PM] jeff101: I wonder how Temple Grandin would do at Foldit.
[3:47 PM] horowsah: someday, it would be fun to create some fictional Foldit accounts of long-dead people we'd like to project how they'd be at Foldit. Like Picasso. I really want to see what proteins he'd design.
[3:47 PM] donuts554:How well can proteins conduct electricity?
[3:48 PM] horowsah: proteins are usually semi-conductive. DNA is actually a better conductor, if I recall correctly. I think that's actually a strategy used to find damage in DNA- shoot an electron down it and find where it stops, and that's the damage site
[3:50 PM] HuubR:Interesting. How do we know where the electron has stopped, can you see a space charge in an electron microscope?
[3:51 PM] horowsah: this has been a few years since i heard about it, but it's a protein that can shoot the electron down, and then another protein recognizes an extra electron elsewhere. That's assuming I'm remembering this correctly. It's a natural dna repair system.
[3:52 PM] HuubR:Amazing! :-o
[3:52 PM] donuts554:Thats somewhat interesting
[3:54 PM] pc:Hi. do we have some news in linker puzzle lab tests ^^
[3:54 PM] alcor29: Can shorter wavelengths be tried? short wave lazers?
[3:54 PM] alcor29:*lasers
[3:54 PM] horowsah: pc- sorry, i don't have any updates there, but i can pass along the request.
[3:55 PM] horowsah: alcor- can you clarify that a bit more?
[3:55 PM] pc: thanks ^^
[3:55 PM] alcor29: Don't know what you're using to get the densities. Assuming like shooting a target with x-rays.
[3:56 PM] donuts554:What things would you encourage Foldit players to do, and what things would you discourage Foldit players to do?
[3:56 PM] horowsah: ah yes- changing the wavelength helps for identifying things like ions and sometimes for phasing (not always), but it won't help with resolution usually
[3:57 PM] horowsah: donuts- probably others would answer the same thing: be creative and think outside the box. don't do the same thing as always, and don't just find one thing and keep drilling on it forever. try new things.
[3:57 PM] Susume (she/her): do you ever shoot the same sample with a series of different wavelengths to "see" different things?
[3:57 PM] alcor29: ditto
[3:57 PM] HuubR:What sort of wavelength is being used, is that X-ray, or gamma, ...?
[3:58 PM] horowsah: susme- yep, we do that. the crystal will degrade, so we try not to do it too much
[3:58 PM] horowsah: so there's x-ray crystallography, and then there's also neutron crystallography where we actually shoot the crystals with neutrons
[3:58 PM] horowsah: turns out you can see hydrogens when you do that, whereas in x-ray crystallography you almost never can
[4:00 PM] Susume (she/her): in foldit densities we don't see the hydrogens but we can sometimes see density for some of the Hbonds, which is cool
[4:01 PM] horowsah: yep, in better ED that does happen
[4:01 PM] horowsah: ok, it's time for me to jet. thank you all for the great questions!
[4:01 PM] Susume (she/her): thanks for the free master class
[4:01 PM] alcor29: Thanks horowsah. Appreciated.

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office hours 7/12/21- led by sciren

[1:02 PM] dudit: (he/him) When is the Office Hour started?
[1:02 PM] jeff101:Josh, what will you be studying?
[1:03 PM] sciren(he/him): Opens office door
[1:03 PM] sciren(he/him): How about now
[1:03 PM] jeff101: @sciren: do you have any news for us? Like what aspects of FOldit are you working on?
[1:03 PM] sciren(he/him): By office door I mean open area table where I can get some sunshine, but same thing.
[1:07 PM] sciren(he/him): Just to give a little info, I as well as our team, are working hard to update the Small Molecule Builder so that we can get going with some small molecule puzzles. Which I very much hope you will all enjoy. Feel free to ask me any questions, and I will try to answer them.
[1:09 PM] sciren:(he/him) For those of you who may not have seen the design we are working towards, I will share it:
[1:09 PM] jeff101: do you mean like Puzzle 1855 Ligand Design ?
[1:10 PM] dudit (he/him): @sciren I think the UI/UX needs a 'Mini Objectives' hover window, from @Formula350 idea design
[1:11 PM] sciren(he/him): Jeff101 similar to that one, but where that one uses the reaction design(which we are still planning on using in the future) This builder works in a more atomistic approach with the option of fragment addition.
[1:13 PM] sciren(he/him): Good point @dudit there are some general UI changes in the works, and the Objectives panel is one of them that will be getting a bit of a makeover.
[1:16 PM] HuubR: I love the idea of the Objectives panel. Will it also be possible to move it into the corner, top left or top right?
[1:18 PM] sciren(he/him): Currently, one of the issues with the Objectives panel is that, in it's expanded form, it obscures the structure you are working on. So to help with that, a movement of the panel to the left-hand side of the screen in development.
[1:19 PM] jeff101:being able to move it would help. It is often in the way if I want to make a screenshot to post on the wiki.
[1:19 PM] jeff101:if you can move it, you could show the same info with less screenshots
[1:21 PM] jeff101:will you be adding LUA commands to tell atom types within a segment # (the segment could be a ligand molecule or an amino acid) ?
[1:21 PM] sciren(he/him): Indeed Jeff101, and we are looking to simplify the menu to show only the directly pertinent information(where scoring is involved), with the ability to get more information should you want it.
[1:22 PM] jeff101: GetAtomType(segnum,atomnum). Have it return C N O S H for amino acid atoms, for example.
[1:24 PM] jeff101: for ligands, perhaps do more complicated atom names, like you might find in a pdb file. They could help distinguish carbons in C=O from carbons with 4 single bonds, for example.
[1:25 PM] sciren (he/him): Currently that isn't in development, but I can definitely take a note of it, and discuss it with the team to see what can/should be done.
[1:25 PM] sciren (he/him): Thank you for the suggestion!
[1:26 PM] jeff101:or be able to query what atoms each atom in a ligand is bonded to
[1:27 PM] HuubR: Would this GetAtomType(segnum,atomnum) also account for different numbers of atoms, e.g. for the first and last segments, or with disulfide bonds?
[1:28 PM] jeff101:and for each atom listed, it could list the type of bond used to connect the atoms: single, double, triple bond, aromatic ring bond (somewhere between single and double bond), etc. maybe it could be a # like 1 of single bonds, 2 for double bonds, 3 for triple bonds, and non-integers for bonds in between
[1:30 PM] jeff101:maybe hydrogen bonds and disulfide bonds would have their own types
[1:32 PM] sciren(he/him): For scripting purposes, I can definitely see why the "more information the better" We will have to look at what would be needed to provide this. I really like the idea of being able to get/share this information on an atom by atom basis.
[1:36 PM] jeff101:it would be nice to be able to measure the distances between atoms on the same ligand. also would be good if we could add bands between atoms on the same ligand.
[1:38 PM] sciren(he/him): Good call Jeff101! These were actually a couple of features that have been discussed based on preliminary testing and both of these items are actually being looked into.(edited)
[1:41 PM] jeff101: that's good
[1:43 PM] jeff101: are there good rosetta forcefields for general small molecules and ligands?
[1:45 PM] jeff101: can they handle metals (copper, iron, zinc), calcium, sodium, or free radicals ?
[1:49 PM] sciren(he/him): That is a good question jeff101. Unfortunately I am not the best versed in the Rosetta force field and its limitations. I know that the force field that is being used better that previous iterations for small molecules. I will looks into it and let you know what I find.(edited)
[1:52 PM] jeff101:are you at Vanderbilt? what is your training?
[1:56 PM] sciren(he/him): I am indeed! So a little about my background: I spent some time outside of the academic world(mostly in the service industry) and eventually decided to go back to school and finish my chemistry degree. Along the way I realized I was very interested in computer science. So I thought why not just do both? I engaged in undergraduate research that was pairing gaming technology, and molecular modeling software, and loved the work I was doing. So when I graduated, I threw a long shot search into google for jobs involving video games and chemistry, and stumbled upon a job listing to work on Foldit.
[1:58 PM] sciren (he/him): Now I get to combine two of my favorite things: Gaming and science.
[1:59 PM] jeff101: that's good
[2:01 PM] sciren(he/him): What's also good is all of the amazing solutions to very challenging problems that you all come up with. It is an absolute joy to see what you all come up with.
[2:01 PM] jeff101:when do you think the next reaction design / small molecule design puzzle will be ?
[2:02 PM] sciren (he/him): We're hoping to get it out to you all as soon as we can, but there are some items to take care of before then.
[2:02 PM] Josh jeff101 sorry, I was in a meeting. Just got your question on what I'm studying. I'll be overhauling the tutorial based on the latest and greatest research in instructional design theories, so I'll need to ask some veterans to walk me through their strategies so I can teach how the pros play.
[2:03 PM] dudit(he/him):( How about more COVID puzzles?
[2:04 PM] jeff101:sounds good, Josh
[2:05 PM] Nicm25: Oh, was that office hours?
[2:06 PM] jeff101:yes Nicm25
[2:06 PM] jeff101: got any questions for Josh or sciren:?
[2:06 PM] sciren(he/him): @dudit I'm not sure about any COVID puzzle on the horizon, but that can be subject to change.
[2:07 PM] sciren(he/him): Yes indeed. I can hang around for another couple more if you have any Nicm25
[2:08 PM] Nicm25:I just joined IRC and missed conversation...lol
[2:08 PM] jeff101: sciren is working small molecule design tools for Foldit. Josh is working on Foldit Tutorials and teaching new players how to play.
[2:10 PM] dudit (he/him): @sciren small molecule design COVID puzzle?
[2:12 PM] sciren(he/him): @dudit currently not that I know of, but that can be subject to change.
[2:13 PM] sciren(he/him): I do want to thank everyone for the questions and suggestions. I'm going to leave my sunlit office for one with less windows, and more coding. I hope you all have a great one, and happy folding!
[2:13 PM] jeff101:thanks for coming. Have a good day.
[2:13 PM] dudit (he/him): Thank you so much @sciren

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office Hour 8/8/21: led by bkoep

[10:59 AM] bkoep: Hello all, and welcome to Foldit Office Hours!
[11:00 AM] Dudit (he/him): Hi @bkoep
[11:00 AM] cjddig (he/him): Hello bkoep!
[11:00 AM] alcor29:Good morning @bkoep. 1. What is the correlation between confidence and similarity? What exactly is the difference between them? Why in your blog fig.3 did you choose to test with confidence and not similarity? Is confidence based on the similarity number? If so why not just use similarity? 2. Can you respond to Boots' comments on the AF blog, please? https://fold.it/portal/node/2011929
The AlphaFold prediction tool in Foldit
The AlphaFold prediction tool in Foldit
[11:00 AM] bkoep: How are people finding the new AlphaFold tool?
[11:00 AM] donuts554: hello
[11:00 AM] alcor29: Murky.
[11:02 AM] spvincent: hi bkoep
[11:03 AM] donuts554: I havent tried the new AlphaFold tool yet
[11:03 AM] spvincent: It seems to work very well, assuming the predictions are accurate. Apart from some solutuons crashimng when you try to load them
@alcor29 Good morning @bkoep. 1. What is the correlation between confidence and similarity? What exactly is the difference between them? Why in your blog fig.3 did you choose to test with confidence and not similarity? Is confidence based on the similarity number? If so why not just use similarity? 2. Can you respond to Boots' comments on the AF blog, please? https://fold.it/portal/node/2011929
[11:03 AM] bkoep: 1. Confidence and similarity are not necessarily related. Confidence is unrelated to the structure of your solution, and it depends on your sequence only. Similarity does depend on the structure of your solution. So, you could take a well-folded sequence and paste it onto an extended chain, and it would have high confidence but low similarity. If you folded up that sequence and ran it again, the second run would give you the same confidence (because the seq is the same) but the similarity should be higher (if it is folded correctly)(edited)
[11:04 AM] Dudit (he/him): @bkoep Is it better to further developing RoseTTAFold to be better at Protein Design puzzle accuracy?
[11:05 AM] bkoep: ... Benchmarking AF by the similarity metric is not so informative, since there is an easy way to game the similarity metric without improving your design (just load an AF prediction, submit it again, and you will get very high similarity)
[11:06 AM] cjddig (he/him): 1. Will AlphaFold work if binder is too far from target? Can it automatically make binder closer to target? 2. Does AlphaFold consider Objectives? 3. Why does AlphaFold solution have some clashes? Doesn't it optimize the protein?
[11:06 AM] BletchleyPark: To what would this be similar ?
[11:07 AM] spvincent: Is there a need anymore for some of the filters in design puzzles? Ideal Loops, Core, etc. could all be handled by AF
[11:07 AM] Dudit (he/him): @bkoep Is it possible that a protein has a 100% confidence & 100% similarity?
[11:08 AM] bkoep: Ah yes, I hadn't seen Boots' comment yet. The short answer is that AF is probably just highlighting some Foldit quirks. I will write out a fuller response after the office hour.
[11:09 AM] alcor29: When you say structure do you mean just the helix, strand or the actual tertiary fold? How does it measure this. ?
[11:09 AM] Dudit (he/him): @bkoep What's the difference between AlphaFold2 vs RoseTTAFold?
[11:10 AM] alcor29: Same thought as spvincent. Use AF to handle loops etc.
[11:10 AM] BletchleyPark: @bkoep Is this correct: AF bases its design on the sequence only. While designing a backbone, changing the sequence through mutating will change the AF prediction and thus the backbone.
@Dudit (he/him)
@bkoep Is it better to further developing RoseTTAFold to be better at Protein Design puzzle accuracy?
[11:11 AM] bkoep: There are machine-learning (ML) scientists always working to improve RoseTTAFold and new algorithms for protein design! AlphaFold2 and RoseTTAFold are both neural networks, but their precise architecture is very different. Unfortunately, I don't have enough background in ML to explain the full differences between the two. I think there are some informative blogs out there that may help you understand the nuances of these networks, for example Mohammed AlQuraishi's blog here: https://moalquraishi.wordpress.com/2021/07/25/the-alphafold2-method-paper-a-fount-of-good-ideas/
Some Thoughts on a Mysterious Universe
Mohammed AlQuraishi
The AlphaFold2 Method Paper: A Fount of Good Ideas
Just over a week ago the long-awaited AlphaFold2 (AF2) method paper and associated code finally came out, putting to rest questions that I and many others raised about public disclosure of AF2. Alr…
@cjddig (he/him)
1. Will AlphaFold work if binder is too far from target? Can it automatically make binder closer to target? 2. Does AlphaFold consider Objectives? 3. Why does AlphaFold solution have some clashes? Doesn't it optimize the protein?
[11:13 AM] bkoep: 1. Right now, it doesn't matter if the binder is far from the target in your Foldit solution. We are only passing the binder sequence to AlphaFold, so it doesn't know anything at all about the target. There are other researchers developing new ways to use AF with binder design (i.e. ways that do include the target) so that AF can predict not only binder folding, but also the binding of the two separate chains.
@cjddig (he/him)
1. Will AlphaFold work if binder is too far from target? Can it automatically make binder closer to target? 2. Does AlphaFold consider Objectives? 3. Why does AlphaFold solution have some clashes? Doesn't it optimize the protein?
[11:15 AM] bkoep: 2. No AF does not consider Foldit Objectives in any way. When you upload a solution for AlphaFold, we simply extract the sequence of your solution and pass that as input to the AF algorithm. Then the AF algorithm spits out a predicted structure, and we send that back to your Foldit client.
[11:16 AM] alcor29: So I get why AF gets a confidence number. Still not clear about why similarity matters then?
@cjddig (he/him)
1. Will AlphaFold work if binder is too far from target? Can it automatically make binder closer to target? 2. Does AlphaFold consider Objectives? 3. Why does AlphaFold solution have some clashes? Doesn't it optimize the protein?
[11:17 AM] bkoep: 3. No, we are only running the raw AlphaFold neural network, and we leave the optimization to you! The AlphaFold team recommends some form of optimization on raw predictions (in CASP they used the Amber molecular dynamics force field). So the clashes are to be expected.
[11:18 AM] Dudit (he/him): @bkoep Should we aim to design a protein that has a 100% in both of confidence & similarity?
[11:19 AM] alcor29:Also, I mutate many times during a design after some things change. But I see you prefer just sending after the final mutate, but, the AF return may cause me to mutate again. Is this a problem for you?
spvincent: Is there a need anymore for some of the filters in design puzzles? Ideal Loops, Core, etc. could all be handled by AF
[11:20 AM] bkoep: This is an interesting question (Do we still need filters in design puzzles?)... Maybe not, if the AF predictions are accurate enough and Foldit players are able to work with AF. Currently, my impression is that the AF outputs are pretty opaque, and don't give much feedback about how a problematic design might be improved. We have some ideas about this, but for now I think the Objectives are still effective guidelines to help new players come up with reasonable designs.
@Dudit (he/him)
@bkoep Is it possible that a protein has a 100% confidence & 100% similarity?
[11:22 AM] bkoep: No, I don't think you would ever see an AF prediction with 100% confidence (although I'm not certain whether this is theoretically possible with the network). The highest I've seen for a designed protein is about 95% confidence.
[11:22 AM] Vincera:I had a 96.8 on one transition.
[11:22 AM] alcor29: Just a thought: Can the aa mutate load for each puzzle be loaded with AFs high confidence loop structures?
When you say structure do you mean just the helix, strand or the actual tertiary fold? How does it measure this. ?
[11:24 AM] bkoep: Sorry, I just saw this followup... AF similarity is measured against the entire protein fold (i.e. tertiary structure). In this case we are using a similarity metric called lDDT (local distance difference test. I think?) that computes the internal distance between all (i,j) residue pairs and compares that against the internal distances in the reference structure
[11:25 AM] BletchleyPark: @bkoep, how many GPUs are ussed to infer the structure for a given sequence ?
[11:25 AM] Vincera:Have you viewed the AF submissions from yesterday (eg, my 96,8 transition)?
[11:25 AM] BletchleyPark: and thank you for the similarity answer
@bkoep Is this correct: AF bases its design on the sequence only. While designing a backbone, changing the sequence through mutating will change the AF prediction and thus the backbone.
[11:26 AM] bkoep: Yes! The output prediction from AF depends on sequence only. If you fold up the same sequence in multiple ways, you will get the same prediction and confidence every time (but similarity will differ). As soon as you make one mutation, you can expect a different prediction from AF.
[11:27 AM] BletchleyPark: thank you ! @bkoep, how long did it take you to train the network (on how many GPUs)and did you use the entire PDB for this ?
@alcor29, So I get why AF gets a confidence number. Still not clear about why similarity matters then?
[11:30 AM] bkoep: Similarity is most meaningful if you have designed your protein completely "blind" to the AF prediction (i.e. 100% in Foldit, without loading AF predictions). Since Foldit and AF are completely independent, this would mean your design is very promising if both Foldit and AF agree (it has a high Foldit score and a high AF confidence). However, if you load in an AF prediction and continue working off of that, future AF similarity metrics will not be as meaningful, since you have now biased your design to be similar to the AF prediction.
[11:31 AM] alcor29: Exactly. So why even bother with similarity figures?
[11:31 AM] spvincent: I'm not sure if the output from AF is opaque. Just loading the solution and toggling back and forth between it and the source (Score/Hydro colouring helps here) gives a good indication of what the problematic areas are.
@Dudit (he/him)
@bkoep Should we aim to design a protein that has a 100% in both of confidence & similarity?
[11:32 AM] bkoep: Most of our experiments so far suggest that 80% AF confidence is probably good enough for protein designs. If you reach 80% confidence, then I would recommend working on a new design!
[11:32 AM] alcor29: Thanks @bkoep.
[11:32 AM] cjddig (he/him): I previously tested AF with triple helices protein which has some threonine on its core, and AF returned a long helix. When we make a unique structure, such as beta helix, is there any possibility that AF would give us totally different structure like that?
[11:32 AM] Dudit (he/him): Thank you @bkoep
@alcor29, Also, I mutate many times during a design after some things change. But I see you prefer just sending after the final mutate, but, the AF return may cause me to mutate again. Is this a problem for you?
[11:33 AM] bkoep: No, that sounds perfectly fine! This is the way we anticipated players would probably use AF (i.e. get an AF prediction, load it into Foldit and mutate/optimize, get another AF prediction, do more mutate/optimization, etc.)
@alcor29, Just a thought: Can the aa mutate load for each puzzle be loaded with AFs high confidence loop structures?
[11:35 AM] bkoep: @alcor29 I'm not sure I understand this question, could you rephrase it? What do you mean by "aa mutate load" and "high confidence loop structures"?
BletchleyPark: @bkoep, how many GPUs are ussed to infer the structure for a given sequence ?
[11:37 AM] bkoep: Right now, we are using a single GPU for inference. It might be an RTX2080 (?), I'm sorry I'm not certain about the hardware
[11:37 AM] alcor29: You know how the table load tells it that GLY, ALA can't be used if the ss is a helix , but it knows that it's OK for a loop. So maybe it can be loaded to recognize this is a loop and only the AF high confidence aas in loops are allowed so it would grey out all the other aas? Like I said . JUst a thought. Might be too complicated to implement?
[11:37 AM] BletchleyPark: sounds good
[11:38 AM] BletchleyPark: sounds like we could run this in our own systems locally
Vincera:Have you viewed the AF submissions from yesterday (eg, my 96,8 transition)?
[11:38 AM] bkoep: @Vincera I have not yet taken a look at the most recent AF submissions. But 96.8% is a very impressive confidence! What kind of fold was this? A helical bundle or something else?
[11:41 AM] Vincera:Quad, from what I recall. I submitted several diif...
@cjddig (he/him) I previously tested AF with triple helices protein which has some threonine on its core, and AF returned a long helix. When we make a unique structure, such as beta helix, is there any possibility that AF would give us totally different structure like that?
[11:41 AM] bkoep: @cjddig, do you mean you tested AF with a natural protein? Note that our "slimmed down" version of AlphaFold will not perform as well as the "official" AlphaFold algorithm that was used for CASP -- especially for natural protein targets.
[11:42 AM] cjddig (he/him): Ah, I designed the protein, not a natural one.
@alcor29, You know how the table load tells it that GLY, ALA can't be used if the ss is a helix , but it knows that it's OK for a loop. So maybe it can be loaded to recognize this is a loop and only the AF high confidence aas in loops are allowed so it would grey out all the other aas? Like I said . JUst a thought. Might be too complicated to implement?
[11:45 AM] bkoep: Ah, gotcha. Yes, that makes sense. Potentially, we can do even better... In principle, we should be able to tweak the AF network so that it returns AA suggestions at each position that would increase its confidence. Very similar to what was reported in the trRosetta energy landscape optimization paper, but this research is ongoing...
@cjddig (he/him)
Ah, I designed the protein, not a natural one.
[11:47 AM] bkoep: We are still learning the limitations of AF, but so far it has been very accurate for small single-domain designs (like the type we are designing in Foldit). If AF predicted a completely different structure for your design, I'm afraid that probably means there are problems with your design. We definitely don't like THR in the protein core, especially for helical bundles...
[11:47 AM] alcor29: Wow.
[11:50 AM] alcor29: Can we have more time for 2029?
[11:51 AM] donuts554: How does the Backbone subscore work in the Foldit scoring system?
@alcor29 Can we have more time for 2029?
[11:51 AM] bkoep: Would more time be useful for reaching designs with better AF confidence? Or is there another reason for more time?
Would more time be useful for reaching designs with better AF confidence? Or is there another reason for more time?
[11:52 AM] alcor29: Only since it's new for us and we are just feeling our way into it.
[11:53 AM] alcor29: For the future. I guess we will see how it goes.
[11:53 AM] cjddig (he/him): My last question: do you think that AF will change the way of folding a lot?
[11:53 AM] CrossedSticks (she/her): Personally I don't need more time, I prefer to tackle a new puzzle rather than keep rehashing the existing ones
[11:54 AM] BletchleyPark: @bkoep, is there away to have the AF result be shown as ready upon completion. I now use reload repeatedly
[11:54 AM] donuts554: I think the AlphaFold feature in Foldit is like a thermodynamic simulating feature in Foldit
donuts554: How does the Backbone subscore work in the Foldit scoring system?
[11:54 AM] bkoep: @donuts554, the backbone subscore evaluates the bond torsions of bonds along the protein backbone. This mostly reflects the (phi, psi) torsion preferences in the Rama Map, but also includes terms to make sure that the peptide bonds (i.e. the bonds between residues) are planar
@cjddig (he/him) My last question: do you think that AF will change the way of folding a lot?
[11:56 AM] bkoep: This is the big unknown! AF definitely promises to open up some new opportunities. For example, I am hoping AF gives us the confidence to branch out into more diverse protein folds (not just helical bundles and ferredoxin-like folds)
[11:56 AM] alcor29: CrossedSticks has a point. I get tired of looking at the same puzzle after a bit.
[11:57 AM] robgee: Will the results of the alphafold puzzles be fed back into the alphafold neural network ?
BletchleyPark: @bkoep, is there away to have the AF result be shown as ready upon completion. I now use reload repeatedly
[11:57 AM] bkoep:
@BletchleyPark, currently there are no notifications for completed AF jobs. If the AlphaFold panel is open, then it will auto-refresh every 30s
[11:57 AM]
BletchleyPark: thank you, that is good to know already
[11:58 AM] Nicm25:(I refrained from asking the question) okay, so if I should use AlphaFold2 on its own to get more detailed information about protein I'm designing, should I use it? as long as AlphaFold's server uses only neural networks, if it can't compensate for interpolated information such as sequence matching and optimization, were we going to get it done? Or was it premature to suggest it? of course, only in puzzles where there is AlphaFold button on foldit. (no need to answer.)(edited)
robgee: Will the results of the alphafold puzzles be fed back into the alphafold neural network ?
[12:01 PM] bkoep: @robgee, that's an interesting idea. The AF network is trained only on experimentally-solved protein structures. I would worry a little bit about including "unverified" protein structures in the training set. I'm not sure if there would be anything to gain from that
[12:09 PM] BletchleyPark: @bkoep, I see a user called AlphaFold has this been a test account
[12:09 PM] BletchleyPark: ?
@Nicm25 (I refrained from asking the question) okay, so if I should use AlphaFold2 on its own to get more detailed information about protein I'm designing, should I use it? as long as AlphaFold's server uses only neural networks, if it can't compensate for interpolated information such as sequence matching and optimization, were we going to get it done? Or was it premature to suggest it? of course, only in puzzles where there is AlphaFold button on foldit. (no need to answer.)(edited)
[12:10 PM] bkoep: Hmm, I'm not sure I follow... Are you suggesting using AlphaFold2 outside of Foldit to improve your design? Technically it is against the Foldit rules to copy a non-Foldit protein into the game, and we encourage players to do all of their work within Foldit (this is important for the integrity of Foldit as a competitive game). But I think you should use whatever tools you want to get ideas about how to improve your Foldit strategies. I see no problem if you want to do some exploring with AlphaFold2 outside of Foldit.
BletchleyPark: @bkoep, I see a user called AlphaFold has this been a test account
[12:11 PM] bkoep: Hmm, I'm not sure. It's not my test account, anyway
[12:13 PM] Nicm25: bkoep, sorry for hassle, and thanks for answering. :-)
[12:14 PM] cjddig (he/him): Thanks for answering bkoep!
[12:14 PM] Dudit (he/him): Thank you so much for the Office Hour @bkoep
[12:16 PM] bkoep: Yes, it looks like my hour is up
[12:16 PM] bkoep: Thanks all for the great questions!
[12:16 PM] BletchleyPark: we had bonus time, thank you !
[12:16 PM] donuts554: You are welcome!
[12:17 PM] bkoep: If you have any more questions, please don't hesitate to post comments on the website. Or you can ping me on Discord!

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Groups: Foldit Staff
Office hour 9/17/21: led by beta_helix and petridecus

[3:02 PM] beta_helix: Hi everyone! Thank you for joining us today for Foldit Office Hours. Andreas just joined the Foldit team, and is working on improving Electron Density Tools (as you can see here, if you are on Discord
[3:03 PM] Dudit (he/him): Hello @beta_helix
[3:04 PM] beta_helix:
Has anyone had a chance to try the new "Select Cloud" devprev feature yet?
[3:05 PM] alcor29: Just tried. And it crashed.
beta_helix: Has anyone had a chance to try the new "Select Cloud" devprev feature yet?
[3:05 PM] Nicm25: I already tried it out 40 minutes ago, with brief review hanging out on this (veteran)channel.
[3:05 PM] beta_helix: Are you in the Selection Interface?
[3:07 PM] alcor29: Nope. Was in original. Will switch. Tx.
[3:07 PM] beta_helix: Whew! Yes, sorry... we should have warned about that (I'll add that to the newspost comments)
[3:08 PM] petridecus: yea we already in the process of removing the option from the original interface, whoops
[3:09 PM] beta_helix: Random poll: How many of you use the Original Interface (most of the time)?
[3:09 PM] spvincent: me
[3:09 PM] Dudit (he/him): me too
[3:10 PM] Nicm25: oops, I'm using the original interface to do protease (cut)
[3:10 PM] beta_helix: Were all of you able to use the Select Cloud feature by switching to the Selection Interface?
[3:11 PM] alcor29: about 50/50 or 60original/40selection
[3:12 PM] alcor29: yup
[3:13 PM] alcor29: I click on select cloud. AAs change color but that's it.
[3:14 PM] spvincent: guess so. not all that familiar with ED puzzles though.
[3:14 PM] beta_helix: @Nicm25 you already posted you thoughts on the tool. Is anything missing or do you have any suggestions on how it could be improved?
[3:15 PM] Nicm25: I refrained from speaking until the documentation was in perfect order, which is bit of surprise!?
[3:16 PM] Nicm25: today, for some time we have not had any density puzzles posted, so I don't think players will be able to answer about this.
[3:17 PM] beta_helix: We wanted all your thoughts before posting it to main, which is when we release the documentation.
[3:17 PM] beta_helix: You are right, I should have pointed out the Beginner ED Puzzle [3:17 PM] beta_helix: Sorry about that, I forget that everyone has that checkbox turned off!
[3:18 PM] petridecus: the beginner ED puzzle is perfect for testing out this tool, that's what i used while i was developing the feature as well
[3:19 PM] alcor29: Trying to follow the petridecus gif, but no luck. Missing an action somewhere.
[3:20 PM] Nicm25: ummm, I am still testing with 2007 and even older puzzles on how I can go beyond algorithm I came up with, solutions I solved manually. ;D
[3:21 PM] beta_helix: @alcor29 what OS are you on?
@alcor29: Trying to follow the petridecus gif, but no luck. Missing an action somewhere.
[3:21 PM] petridecus: what's the issue that you're running into. are the residues not being selected?
@Nicm25: ummm, I am still testing with 2007 and even older puzzles on how I can go beyond algorithm I came up with, solutions I solved manually. ;D
[3:21 PM] beta_helix: We hope to provide even more ED tools soon
[3:21 PM] alcor29: Win10
[3:22 PM] petridecus: yeah there's a lot more useful stuff that's already in the works!
[3:22 PM] alcor29: Cannot select pieces of the cloud as in the gif
[3:23 PM] petridecus: @alcor29 so you press the button and nothing happens then?
[3:24 PM] alcor29: Nope. the colors change but you seem to be selecting the area you want by moving the protein. I try that and nothing happens. Even though I also clicked center on density.
[3:24 PM] petridecus: the area of selection does not move until you press the button again
[3:25 PM] alcor29: No. If it works for everybody else we should go on. Eventually I'll figure it out.
[3:26 PM] beta_helix: Well, this is helpful... because we need to make sure it is clear and easy to use for everyone
[3:26 PM] alcor29: OOps just got it o work I think I need to double click.
[3:26 PM] beta_helix: Yay!
[3:27 PM] alcor29: OK. It highlitghts different sections but the cloud does not change so what is gained?
[3:28 PM] alcor29: Must still be missing something.
[3:28 PM] beta_helix: That's why were are here
[3:30 PM] alcor29: Do I need to change my radius and thresholds to see the effect?
[3:30 PM] petridecus: in short, it's using the cloud as a means to select and then focus your wiggle/shake operations on a particular region of the protein

[3:30 PM] petridecus: the goal is not to change the cloud itself or anything like that
[3:32 PM] petridecus: the cloud is a very visually informative element to the puzzles in which it's present- we believe that also being able to select regions using that visual element could make it even more useful
[3:33 PM] HuubR: Please correct me if I'm wrong; I'm not sure I understand this correctly. When using Selection Interface, the [Select Cloud] button will select all residues that are within the cloud, and deselect all that are outside?
[3:34 PM] petridecus: yup that's correct!
[3:34 PM] alcor29: Agree. But don't see any changes in the cloud so maybe 2007 shows no effect because it is already about as centered as it can be?
[3:35 PM] alcor29: Looking for different ed puzzle.
[3:35 PM] petridecus: again, the goal is not to change the cloud itself. not sure if i understand your question
[3:35 PM] alcor29: Beginner.
[3:36 PM] HuubR:But when I move the entire protein out of the cloud, and then press the button, it still selects everything (157 residues in the Beginner puzzle). What am I doing wrong? Wrong OS (Win 8)?
[3:36 PM] alcor29: OK, I don't have a beginner ED puzz on my list.
[3:37 PM] petridecus: @alcor29 make sure you've checked the box to show beginner puzzles
HuubR:But when I move the entire protein out of the cloud, and then press the button, it still selects everything (157 residues in the Beginner puzzle). What am I doing wrong? Wrong OS (Win 8)?
[3:37 PM] petridecus: that may be a bug! i'll try to reproduce it
[3:37 PM] alcor29: yup all checked beginner, expired etc.
[3:38 PM] alcor29: 2007 was the only ED on my menu
[3:39 PM] beta_helix: Staphylococcus Aureus Electron Density
[3:39 PM] beta_helix: strange, I thought those were available to all players
[3:40 PM] alcor29: Staph works. ED description ran off the page.
[3:40 PM] beta_helix: woo-hoo
[3:42 PM] beta_helix: @HuubR any other feedback or possible bugs?
[3:42 PM] alcor29: OK. Seems to working. Sorry.
[3:42 PM] HuubR:No, not yet. I just found the puzzle 15 minutes ago :-)
@alcor29 OK. Seems to working. Sorry.
[3:43 PM] petridecus: if there are issues that were specifically happening in the 2007 puzzle that would still be good to know. is the tool behaving differently between the two puzzles?
[3:45 PM] Nicm25: in my environment, it worked without any problems, as far as I understand.
@alcor29 OK. Seems to working. Sorry.
[3:45 PM] beta_helix: No worries at all. Thank you! We clearly want to post a detailed description of this before it goes to main (ie in a blog or on the wiki)
[3:47 PM] alcor29: @petridecus Can't really say. But I didn't see any effect that was new on 2007
[3:47 PM] alcor29: It will take a while before I actually understand this by fooling around with it a bit.
[3:48 PM] Nicm25: well, I would like to ask question about direction. do we want tools to change the pose of proteins based on their density? or do we want tools to make the density more visible or new ways to draw it?
[3:49 PM] beta_helix: @Nicm25 Great question! What do you think?
[3:51 PM] Nicm25: Ah, I wanted to ask about which is priority, I can give idea but I need to put it together as documents.
[3:52 PM] petridecus: current development, including this tool, are definitely leaning more towards the "changing the pose" direction
[3:52 PM] alcor29: Bottom line question? How is this expected to improve ED folding?
[3:53 PM] jeff101: how do all the copies of the ED that we can't see affect the results of the Select Cloud tool?
[3:53 PM] alcor29: A specific example.
[3:54 PM] petridecus: @alcor29 it's a tool that we hope will give players more precision when working on certain regions of the protein- when doing wiggle/shake operations in particular
[3:55 PM] Nicm25: (my concern was whether or not I could provide new 'fair tool'. so I am in process of sifting through ideas to pass on to new developers.)
[3:55 PM] petridecus: if someone is looking at a certain region of the protein and wants their operations to only affect that region, it's now as simple as moving the cloud over that area and pressing the select cloud button
[3:56 PM] beta_helix: especially when we give you giant electron density clouds!
[3:56 PM] jeff101 if we select region A of the visiblecloud, is it also selected in all the hidden clouds? then, if the protein is extended so it crosses multiple copies of region A of the ED cloud, will multiple chunks of the protein get selected too?
[3:57 PM] jeff101 not just the part of the protein in the visible copy of region A of the ED cloud?
[3:57 PM] petridecus: i don't understand this question. when you refer to hidden clouds, do you mean the different display options for the cloud?
[3:57 PM] jeff101: if you drag the protein thru seeminly empty space, you will find many regions wth nonzero ED
[3:57 PM] petridecus: i can say this for sure though- once the residues are selected based on the location of the cloud, the selection is no longer dependent on where the cloud is
[3:57 PM] beta_helix: @jeff101 the symmetric copies of the cloud should stay the same
[3:58 PM] beta_helix: but that is a good question about what remains selected...
[3:58 PM] beta_helix: we'll have to check that, but my guess is that only the "selected protein" actually gets selected
[3:58 PM] beta_helix: @jeff101 have you had a chance to try it out yet? If so, thoughts?
[3:59 PM] jeff101: the protein can straddle more than one ED cloud. part of the protein can be in the visible ED cloud. other parts of the protein can be in the hidden ED clouds.
[3:59 PM] jeff101: I have not tried the new ED tools
[3:59 PM] beta_helix: right... but the selected region, should only be what you see. Key word being "should"
[4:00 PM] beta_helix: Got it. Just curious, as I know you have many ED suggestions.
[4:00 PM] beta_helix: petridecus has your wish list
[4:00 PM] jeff101: that's good
[4:01 PM] alcor29: @petridecus when you say move the cloud over an area what do you mean. I can move the area to the cloud but not vice versa.
[4:01 PM] HuubR: jeff101, when you move the protein out of the ED cloud, you will see the score drop. Have you seen it go up again when the protein was not in the visible cloud?
[4:01 PM] beta_helix: Yes, HuubR, that is possible.
[4:01 PM] petridecus: when you move the focus of the camera over a certain region of the protein, thus causing that part of the cloud to be visible @alcor29
[4:01 PM] alcor29: Suggestion: I think a live demo would be most usefull
[4:02 PM] beta_helix: Great idea!
[4:02 PM] beta_helix: Andreas, you down for that before this goes to main?
[4:02 PM] jeff101: I have seen the score rise and fall and rise again when I drag the protein through space
[4:02 PM] petridecus: yeah absolutely
[4:02 PM] beta_helix: Sweet... sounds like a plan.
[4:03 PM] beta_helix: Thank you all for your feedback on this, and for stopping by today's Office Hours.
[4:03 PM] alcor29: Thank you all.
[4:03 PM] beta_helix: Unless there are any last questions...
[4:03 PM] jeff101: crystals are periodic structures. for simple ones like salt, there are unit cells
[4:03 PM] petridecus: thanks everyone!
[4:03 PM] Dudit (he/him): Thank you @beta_helix @petridecus
[4:03 PM] jeff101: the unit cells repeat in all directions
[4:03 PM] Nicm25: thank you very much.
[4:04 PM] jeff101: yes, thanks
[4:04 PM] HuubR:Yes, thank you all :-)
[4:04 PM] beta_helix: @jeff101 sometimes what we do is add a buffer in between them... but that makes the density file even bigger
[4:04 PM] beta_helix: Thank you all.. and keep up the great folding!

agcohn821's picture
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Groups: Foldit Staff
Office hour 10/23/21- led by jflat06

[1:04 PM] jflat06: Alrighty, hello everyone, and welcome to office hours! I'm jflat06, a developer on Foldit. I work on the software side of things for both the client and server. I don't have anything specific to talk about today, so if you have any questions or topics, feel free to bring them up
[1:05 PM] spvincent: hi jflat. I'm wondering if you're making progress on fixing the problems with small molecule design
[1:09 PM] jflat06: While I don't work on that specifically, I know that those are actively being worked on. I think we have 1 fix waiting already, and more should be coming soon as well.
[1:09 PM] spvincent: ok, tx
[1:11 PM] jflat06: We have several developers who are dedicated specifically towards development on the small molecule design stuff
[1:11 PM] spvincent: i know from experience how hard it is to track down irreproducible bugs
[1:13 PM] jflat06: Yeah! It's definitely a nightmare sometimes
[1:14 PM] jflat06: We have been trying to add more debugging info over the years to help with these things, but it's always a tough problem
[1:15 PM] jflat06: One of the features for the new site that I'm really looking forward to is the ability to download and install any old version of the client, which will be amazing for enabling players to help track down bugs for us
[1:15 PM] pc: Hi. AlphaFold tool is very interesting and helpfull in puzzles. Will you add some additional informations in AlphaFold prediction, like confidence detail in each segments (with color for exemple) ?
[1:15 PM] jflat06: @pc definitely
[1:15 PM] jflat06: We have some things in mind, and we hope those features will be coming sooner than later
[1:16 PM] spvincent: Perhaps you could look into sending out versions which display more debug info: stack traces and the like.
[1:16 PM] pc: I saw this in a scientific software video (it is confidence color)
[1:16 PM] jflat06: There are some technical hurdles to overcome to communicate that info between the client/server
[1:17 PM] jflat06: Yup! The stuff we're looking at specifically is giving you confidence on a per-residue basis
[1:17 PM] LociOilingIRC: do we have any ideas on why sometimes the traceback info on windows is all zeroed out?
[1:17 PM] jflat06: You mean the crash stack traces?
[1:18 PM] jflat06: Unfortunately I'm not sure
[1:18 PM] LociOilingIRC: yes, seems like something must have zapped memory
[1:18 PM] LociOilingIRC: also sometimes we get a debug.txt after a crash, but often we don't
[1:19 PM] jflat06: Yeah, the crash reporter tries to get that stack trace, but some crashes are just 'segfaults', where the crash reporter never even gets a chance to grab that stack trace
[1:19 PM] jflat06: and unfortunately not much we can do in those cases
[1:20 PM] LociOilingIRC: ok, that makes sense
[1:20 PM] spvincent: Maybe there are better tools on other platforms
[1:21 PM] pc: Thanks. In foldit it is hard to visualize clashes and voids with details. to optimise packing we mostly use script and not enough hand folding. So maybe we need this kind of visualisation : (edited)
[1:23 PM] pc: with a volumetric cloud in a 3d texture
[1:26 PM] jflat06: I know we have the isosurface, but I realize that is a little... lacking
[1:29 PM] LociOilingIRC: just thought of this again, but would it be possible to have a protein design sandbox with alphafold?
[1:29 PM] spvincent: I was thinking the same thing!
[1:29 PM] LociOilingIRC: puzzle 2027 can be used up to a point, but it has a limit of 120 segments
[1:30 PM] pc: Do you know if players use AF in puzzles ? I saw some top score players forgot to use it. Maybe score system can take count about some protein analysis in shared solutions ?
[1:30 PM] LociOilingIRC: also, AF seems doubtful about some real proteins
[1:31 PM] pc: yes LociOilingIRC ^^. I experiment new proteins in a design puzzle round begin. But can be interesting in sandbox yes ^^.
[1:31 PM] LociOilingIRC: for example, I just submitted the zinc binding protein, and the prediction came back with only 60% confidence
[1:31 PM] spvincent: I don't think its a question of forgetting to use it.
[1:32 PM] LociOilingIRC: not forgetting, sometimes you just have to move on without AF
[1:33 PM] spvincent: I suppose at some point the AF score might get integrated into the Foldit score but i've no idea how that could reasonably be done.
[1:33 PM] jeff101:I've had solutions that start with good AF scores, but as they gain Foldit points, the AF confidence score goes down.
[1:33 PM] pc: sometimes we have to reduce points to get better confidence. Score system can be adapted maybe.
[1:33 PM] alcor29: Hi jflat06. would you know if foldit will work with Windows 11?
[1:33 PM] jflat06: I don't run the puzzles, but we might have some plans for that in the future with a setup like the competition we ran earlier this year where you try to get as many viable solutions as possible.
[1:33 PM] jflat06: @alcor29 I have no idea :x
[1:34 PM] jflat06: I don't think anyone on the team has upgraded yet
[1:34 PM] alcor29: k
[1:34 PM] alcor29: Tx.
[1:35 PM] pc: In binder puzzles when we adapt too mush our protein to target, the alone protein become less stable alone. it is normal. For the first time we can know when it happen with AF. But we can need an objective in game that tell us when out protein is to mush twisted. (edited)
[1:35 PM] jeff101:is AlphaFold based just on structures of monomeric proteins that contain no metals, ligands, or other cofactors and are not part of larger protein complexes?
[1:36 PM] jeff101:is AF based only on structures in the physiological pH range that most FOldit puzzles are done at?
[1:37 PM] pc: In last puzzle I maybe found a protein that keep his hight confidence during all round (91.5%). It is because I talked it to bko-ep this week ^^
[1:37 PM] jeff101:are any of the structures AF is based on membrane proteinns? are any in environments that favor disulfide bonds? are any in environments that disfavor disulfide bonds?
[1:38 PM] jflat06: I'm not sure about what training data was used to train alphafold
[1:38 PM] jflat06: I think the paper would be the best place to look up what training set they used
[1:40 PM] jeff101:it would be nice to be able to color residues by any subscore we choose. This would give a different perspective on things like packing, voids, and clashing.
[1:41 PM] jflat06: Yeah, that would be a cool feature. I know we have some plans for re-doing some of the visualizations, and that might be something we try and work in
[1:41 PM] jflat06: no timeline on that, though
[1:42 PM] jeff101:it would also be nice if we could access the # of neighbors Rosetta/Foldit uses to decide which residues are in the core
[1:42 PM] alcor29: Will any work on the new client be directed to improving the hypersensitivity of the move tool?
[1:44 PM] spvincent: this may be off topic a bit, but what will Rosetta be doing in this new era of AF and the Rosetta equivalent? looking at proteins with non-canonical amino acids: that kind of thing?
[1:45 PM] jeff101:can you cite a paper or web page that gives more details about how Rosetta/Foldit uses cones to find the # of nearest neighbors to a residue? I would guess that the cone angle and size depends on what amino acid a residue is. Things like glycine and alanine would have smaller cones than tryptophan for example. If we knew all the angles and distances involved, we might be able to code our own neare
[1:45 PM] jeff101:st neigbor calculator with LUA
[1:45 PM] jflat06: @alcor29 can you describe the problem more specifically? Is the rotation too sensitive?
[1:46 PM] jflat06: @spvincent I don't know all of what is happening on the Rosetta side of things, but I do know that there's a huge rush to figure out how to use and extend the machine learning algorithms, specifically with respect to protein design
[1:47 PM] jeff101:Rosetta@Home is still sending out jobs
[1:47 PM] jflat06: Even from a Foldit point of view, this is super exciting, because it gives us a chance to dramatically increase the odds that your designs will fold up properly by the time they make their way to us
[1:48 PM] pc: rotate around protein in symetric puzzles is not very easy. It is because it depends of protein position I suppose ? When protein is far it is less easy.
[1:48 PM] jflat06: @jeff101, I don't know much about the inner workings of the nearest neighbor calculations, unfortunately
[1:48 PM] jeff101:@pc do you use q to center the rotation on the protein. it helps
[1:48 PM] alcor29: Very hard to impossible to make a slight correction, especially with the gimble function. Can you do something akin to changing the gear ratio?
[1:48 PM] pc: thanks jeff ^^
[1:49 PM] jflat06: yeah I think I know what you're talking about. I think we could improve that, I always found it finicky, but I never actually had to do anything with it!
[1:49 PM] jflat06: I just had to test it... hah
[1:49 PM] spvincent: I can understand how the field has been turned upside down but isn't there a danger of relying too much on AF and abandoning Molecular Mechanics approaches? The latter should be much more general.
[1:50 PM] jeff101:I made a recipe called FindMonomers to help find monomers when they are far apart. It puts some bands between the monomers that you can follow from one monomer to another. It also adds labels to at least one monomer so you can find it using Notes Mode.
[1:50 PM] Vincera: Is there a way for bona fide, regular, independent FoldIt researchers without current instituitonal affiliation or gain access to full-text articles via UW? We often need to read beyond the abstracts and cannot afford 40$ a pop.
[1:51 PM] jflat06: I don't think anyone is abandoning it, but more thinking about when and where it can be integrated to improve existing techniques
[1:53 PM] spvincent: integrated into RosettaFold?
[1:53 PM] jflat06: @vincera Generally, I'm not sure. I think any of the studies related to Foldit we pay to make open-access, though
[1:54 PM] jeff101:Vincera, if you know the title and authors, you can sometimes find pdf's of key articles doing a google search. Some authors post them on their own web pages.
[1:55 PM] Vincera: Scribd and Semantic Scholars offer pdfs but I don;t want someone's hijacked, stolen work.
[1:55 PM] jflat06: There are tons of different methodologies under constant research within the Rosetta community, and I think people are all asking themselves, "how does this fit into my research?"
[1:55 PM] spvincent: Also if you ask the authors for a copy saying who you are and why you want it they'll usually send you a copy.
[1:56 PM] jeff101:back in the day, authors would order hardcopy preprints or offprints that they could mail to colleagues
[1:56 PM] Vincera: Yes; but, as an American citizen, I cannot - for instance - directly request an Iranian article. This week I ahd to do a workaround and access via the Dutch researcher.
[1:57 PM] jflat06: Sometimes that might be, "can I just do this all with machine learning?". But more often I would expect people to ask, "What if this part of my research was a solved problem?"
[1:57 PM] Vincera: And some of the Caribbean Basin works are the most difficult.
[1:57 PM] Vincera: I read the French and Spanish research
[1:57 PM] Vincera: but cannot gain access to the researcehrs themselves often.
[1:58 PM] Vincera: Much of their work has not even made it into the databanks.
[1:58 PM] jflat06: For example, from a Foldit point of view, what if protein structure prediction was a solved problem? How do we redesign foldit with that in mind? We would want to have more of a focus on sequence manipulation and tools to match a sequence to a specific shape.
[1:59 PM] Vincera: I myself am published and had to pay for my own article.
[2:00 PM] spvincent: Perhaps but Foldit has been emphasizing protein design for years
[2:01 PM] alcor29: AF can predict monomers, but we have to change sequences to "bind" with other substances or symmetric copies. That's where I have a problem seeing where AF can help unless it is trained on millions of interfaces?\
[2:01 PM] pc: Foldit is more a "design software" than a "prediction software" now
[2:02 PM] pc: And I think in the future of Foldit we will have design puzzles with proteins that have "functions" (maybe)
[2:02 PM] pc: It will be very interesting ^^
[2:03 PM] jflat06: AF doesn't currently pick shapes that bind to other shapes. But having an oracle that tells you what shape a specific sequence folds up into is still enormously powerful for this task.
[2:03 PM] alcor29: Absolutely.
[2:04 PM] alcor29: Thanks jflat.
[2:05 PM] jflat06: That's never existed in the field before, and rather than viewing it as encroaching, I think most people in the field are beyond excited about how they can apply it to different problems.
[2:05 PM] spvincent: Maybe. I just have reservations about the way AF is sometimes portrayed in popular science websites as being the last word in protein structure prediction. It may be a major advance but ultimately it's pattern matching not science. Even if its the pinnacle of pattern matching
[2:06 PM] alcor29: No doubt. I have a feeling the interface problem will eventually be worked on.
[2:06 PM] jflat06: Sure - but a lot of science itself is pattern matching. Much of rosetta is based on statistical models and trying to emulate patterns.
[2:07 PM] jflat06: I certainly don't think that AF means the end of statistical of physical predictive modelling for protein folding.
[2:07 PM] spvincent: thats good
[2:07 PM] pc: AF give a very important feedback in design puzzles. But yes prediction is not resolved.
[2:07 PM] NinjaGreg: Seems to me what you'd want is a tool that allowed you to specify a fold, and have it tell you the sequence to get there.
[2:08 PM] jflat06: @NinjaGreg that's the holy grail
[2:08 PM] alcor29: That would be great!
[2:08 PM] NinjaGreg: Right now it's sort of "try this and see what happens".
[2:08 PM] pc: NinjaGreg : maybe it is possible yes, most of deep learning algo can be reversed (edited)
[2:09 PM] NinjaGreg: Think the AF people would look at that?
[2:10 PM] pc: https://fold.it/portal/node/2011976 : I made this topic for that @NinjaGreg ^^
[2:10 PM] jflat06: I'm sure they will at some point.
[2:10 PM] NinjaGreg: Hey, thanks pc!
[2:10 PM] jflat06: I'm pretty sure Rosetta people are
[2:10 PM] alcor29: You can have a library of sequences and corresponding folds, even the unconforming ones.
[2:11 PM] jflat06: Ok, I am going to go grab some lunch. Thank you everyone for coming!
[2:11 PM] alcor29: Thanks jflat
[2:11 PM] spvincent: tx jflat
[2:11 PM] NinjaGreg: Thanks for hosting, @jflat06!
[2:12 PM] pc: "bon appétit"
[2:12 PM] pc: thanks
[2:12 PM] Nicm25: thanks very much ^^.
[2:12 PM] jeff101:thanks jflat06

agcohn821's picture
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Groups: Foldit Staff
Office Hour 11/20/21- led by rmoretti

10:59 AM] rmoretti: Hello! rmoretti here for Office Hour. Let me know if you have any questions about Rosetta, Drug Design, the new UI (in devprev) or anything else.
[11:00 AM] cjddig: (he/him): Hello rmoretti!
[11:02 AM] HuubR: Hello @rmoretti :-)
[11:02 AM] alcor29: Good Morning moretti.
[11:03 AM] rmoretti: What do people think about the VHL drug design puzzles?
[11:03 AM] HuubR: Interesting type of puzzle!
[11:04 AM] HuubR: Totally different to what we are used to, though
[11:04 AM] cjddig: (he/him): It's interesting, and I'm enjoying it. But I want to change the direction of carbon chain of the ligand, but it is hard to do. Is there any effective way to do that?
[11:04 AM] pc: hi
[11:05 AM] Nicm25: nice new puzzle types, trying to find it unknown algorithm ;D
[11:06 AM] pc: New Ligand puzzle tools are a lot better than the previous. Off course there is some improvements possible ^^
[11:06 AM] alcor29: Same as cjddig:. We need more functionality. For example can we freeze just one carbon, etc.
[11:06 AM] rmoretti: To move the carbon chain, you can try pulling the ligand to try to get the end bits to move to a different location, but I realize that's not all that useful at the moment. We are thinking about adding a tool which will allow you to rotate bonds, but we don't have it fully implemented yet.
[11:06 AM] alcor29: Hard to manipulate the ligand.
[11:06 AM] HuubR: It feels like I am just trying random things (not having any background in chemistry, except in school, some 40odd years ago :-), to see what works, but I like it.
[11:07 AM] rmoretti: Finer atom-level control (e.g. freezing atoms) is something that would be nice, but it's a bit tough, as Foldit was set up to work mostly on a residue-level basis, not on an atom level.
[11:07 AM] pc: it is now easy to work on our ligand, keeping some bonds. But the may difficulty is to keep something easy to create in lab, and keep low clogp.
[11:09 AM] rmoretti: Striking that balance is what makes the small molecule design process tough (even for experts).
[11:10 AM] rmoretti: We're interested in giving you tools to make it easier, but we recognize we may still have a ways to go.
[11:10 AM] cjddig: (he/him): cLogP is one of the hardest part of playing the puzzle. If I put too much polar atoms, TPSA score goes down; if I remove them, cLogP and synthesizability score goes down.
[11:12 AM] cjddig: (he/him): By the way, how does foldit judge if the ligand is synthesizable? What makes ligand unable to be synthesized?
[11:14 AM] rmoretti: Synthesizablility is a little bit tricky, as often the only way to figure out if something is synthesizable is to show it to a medicinal chemist and ask them to come up with a synthesis scheme. For the synthesizability score, we use a published protocol which is based on looking at small segments of the ligand and ranking them based on how frequently they're seen in drug-like molecules. If a small section of the ligand isn't seen frequently, it means it likley isn't very synthesizable.
[11:16 AM] pc: @rmoretti A little improvement can be better tooltips. The real name of the atom, his main utility. I never understand F I Cl and Br utility for example.
[11:16 AM] rmoretti: That's what the "show" button of the Synthesizability objective is doing -- it's showing those sub-sections of the ligand which aren't seen very often, and are thus contributing negatively.
[11:17 AM] rmoretti: @pc Good point -- the tooltips could have the full element names. (That's a blind spot a chemist has - we know all the abbreviations.) -- By the way, F is Fluorine, I is Iodine, Cl is Chlorine and Br is Bromine
[11:18 AM] pc: Thanks. and a little description on the utility like "interact with watter", or "usefull to create this.."
[11:19 AM] spvincent: I've yet to find a case adding/replacing with these atoms makes a positive difference.
[11:20 AM] HuubR: Has the synthesizability objective been changed after the first round? In p2059, my ligand was synthesizable, and I think I entered exactly the same formula in p2062, but then it was "very likely not synthesizable".
[11:20 AM] alcor29: Why do we begin with lots of Nitorgen, for example, since we will probably have to get rid of them to meet the amide etc. penalties/undesirable group requirements.
[11:20 AM] rmoretti: The "useful to create this" tooltip would be a bit harder, as often those sorts of things are highly contextual. -- It's probably something that would need to be an external resource, sort of like how you learn when Lysine or Asparagine are useful in a protein.
[11:20 AM] Susume: (she/her): maybe a wiki page
[11:21 AM] rmoretti: @HuubR We did make the synthesizability objective a slight bit more stringent in the most recent round.
[11:21 AM] HuubR: :-)
[11:21 AM] cjddig: (he/him): By the way, when I try to put phosphorus, it always say "chemically not feasible." Also, I learned that nitrogen can make bonds up to 5, but it seems to be impossible. Why is that?
[11:22 AM] rmoretti: @alcor29 The molecule we're starting with in the VHL puzzle is a compound from the literature which already has a decent binding. Changing up the compound to meet the various objectives is sort of the goal of the puzzles.
[11:23 AM] spvincent: Broadly speaking, are you looking for a few high-scoring solutions or many solutions with more variety but which perhaps score less?
[11:23 AM] alcor29: In general we add and delete things kind of randomly and see if the score goes up. Maybe that's a good thing for you. Introducing the ignorant human element. Or, maybe we need more chemistry knowledge to do a better job?
[11:24 AM] HuubR: I'm with you, alcor29 :-)
[11:24 AM] rmoretti: Phosphorus has rather different requirements for the number of bonds, so typically if you just want to replace an existing atom with phosphorus it's not likely to work. Adding a phosphate group from the fragments panel is likely the best approach.
You don't typically see nitrogens with five bonds in drug-like molecules, so we've limited it to only having 4 bonds.
[11:26 AM] rmoretti: @spvincent We haven't yet dialed in the scoring function to get compounds which are interesting to show up as high scoring. That's somewhat anticipated in these early stages, but if you're looking for scientific impact, rather than score, trying a variety of different approaches to reach the stated goals of the puzzle (from the puzzle description) is probably the way to go.
[11:26 AM] pc: @rmoretti A little other improvement can be : when we select a new fragment, an UI can show us what fragements are more "likely synthesizable" for exemple.
[11:29 AM] rmoretti: @alcor29 More chemistry knowledge would probably be helpful, just like more biochemistry knowledge is helpful in the protein folding and design puzzles. Citizen science drug design is still in its very early stages, so we're still trying to figure out what's the best level of approach, and how much "expert" knowledge is needed.
We sort-of have the hope that the community can come together to discover what's useful and what's not in their considerations. But if there's something in particular we can do to help out, please let us know.
[11:30 AM] spvincent: You could fix the crashing :)
[11:31 AM] HuubR: I would guess that you adapted the synthesizability objective based on us non-chemists coming up with compounds that a chemist would never think of?
[11:32 AM] alcor29: Yes, it's crashy again.
[11:32 AM] cjddig: (he/him): Is sulfur counted as polar atom or non-polar atom? h TPSA and cLogP highlights sulfur.
[11:34 AM] rmoretti: @HuubR That's a bit what the "Bad Groups" objective is about. Each round we take a look at the compounds which are coming back, and there's frequently something which our medicinal chemist collaborators will highlight as something which Foldit players are producing which a medicinal chemist would never even consider (because it's just not a feasible compound to synthesize).
[11:34 AM] alcor29: Have any of the results so far been of any use to you?
[11:34 AM] rmoretti: @cjddig: (he/him) I haven't dug into the code for those in that detail, but think it's a little bit of h.
[11:37 AM] rmoretti: The results so far have been excellent for showing what we've not been properly considering, and how to make the tools and puzzle setup better.
As far as coming up with compounds to test in the lab, well, to be honest the useful compounds have been relatively sparse. There's been some "oh, that's interesting" results, but not necessarily a large number of "design of the month" type results.
That's okay. We're learning, and hopefully we can adjust things to get better.
[11:39 AM] HuubR: So our (no, let me rephrase:) my ignorance actually helps you improve your objectives? :-)
[11:40 AM] Susume: (she/her): let's call it 'out of the box thinking'
[11:40 AM] HuubR: :-)
[11:40 AM] alcor29: lol
[11:41 AM] cjddig: (he/him): Will there be other ligand design puzzles besides VHL?
[11:43 AM] rmoretti: VHL is the main target our collaborators are interested in the moment. There's a bit of a push to see if we can get a number of testable compounds, at which point we'll send them out to be synthesized and tested. But once we're done with this initial phase of VHL puzzles, we will likely move on to other targets. (Which ones still to be determined.)
[11:43 AM] alcor29: How is the new UI being accepted?
[11:44 AM] HuubR: I think it is a very good idea to migrate to a single interface, but I also think that "migrate" is an important word here. Judging from the present reactions of long time players, who (understandably) prefer the Original Interface, I feel that the present form has (too) much resemblance to the Selection Interface, and therefore is too far away from the Original.
[11:45 AM] rmoretti: It is true that we leaned heavily on the Selection Interface for the new UI. The reason for that was that the Selection Interface was the preferred interface for the internal Foldit team, and because our understanding is that many of the top Foldit players preferred the Selection Interface (though not universally).
[11:46 AM] cjddig: (he/him): The new UI shortcut is more intuitive (Y for mutate but that's okay) but not familiar. For example, C was for cookbook and X was for cut; now, C is for cut.
[11:47 AM] alcor29: The move tool from selection is kind of awkward. you have to pick it up first from the boxes menu and then locate it. Why can't we keep the original UI way in which we just right click on the exact fulcrum that we want and it just pops up?
[11:47 AM] pc: I use the original interface to move the ligand
[11:47 AM] rmoretti: If there are particular issues where you think the new UI is worse than the Original Interface (aside from just being different), please let us know. We don't consider the new interface to be "finished" by any means, so making it better is something we're interested in.
[11:48 AM] HuubR: Would it be an idea to move the new menu from the left hand side to the tom, where the menu tabs are in the Original Interface, and make the order of the buttons correspond to the Original, as far as possible? That way you would make it easier for a lot of players, who rely on "muscle memory" (I have taken this term from Angus's comment)
[11:48 AM] HuubR: https://fold.it/portal/node/2012337#comment-45514
Developer Preview Release Soon
Developer Preview Release Soon
[11:49 AM] cjddig: (he/him): Actually now I got used to Selection Interface and do like it, so overall, new interface is good.
[11:49 AM] pc: For now we have something good ^^. What we need is more some helps ingame for players that doesn't know chemistry very much
[11:49 AM] HuubR: Another proposal I would like to make: put the action buttons along the left hand side, down from the Foldit logo / main menu button. And give three options: show all buttons, show only those that apply in the present context / selection, and thirdly show only the one that is currently running (the "stop spinner"?). I would prefer the third option, because I use the hotkeys, not the buttons.
[11:50 AM] HuubR: That would place the spinner back in the upper left corner, where I think it belongs.
[11:50 AM] cjddig: (he/him): Agree with pc. New players would need some science backgrounds.
[11:51 AM] HuubR: And please show me how many segments I have selected!
[11:52 AM] pc: Maybe for a biochemist it is easy to know where add an nitrogen to improve clogp, but for me, I just randomly try everything.
[11:52 AM] cjddig: (he/him): Some users just play this for fun (like me)... but now I feel like I should know chemistry.
[11:53 AM] Susume: (she/her): I like the idea of letting us pick which buttons to show (all/some/current) - like HuubR I use mostly hotkeys, so buttons are lost real estate - but for many players they are very useful
[11:53 AM] Nicm25: (improve the glossary. to atoms.)
[11:54 AM] cjddig: (he/him): Well, by the way, where is rebuild? I haven't seen the button since the interface update.
[11:54 AM] HuubR: I learned the use of hotkeys from your YouTube video, @Susume :-)
[11:55 AM] pc: Is orange in "sphere view" means that my ligand is too much hydrophobic ?
[11:57 AM] HuubR: I think that is just the colour for Carbon in the ligand, as long as you have not selected a different colour in the View Ligand menu.
[11:58 AM] rmoretti: The coloring should be controlled separately from the display size (though I admit I don't use sphere view much). If you're using Score/Hydro+CPK coloring, I think the orange is more indicative of the score than being hydrophobic. -- Also, if you're using one of the ligand coloring, it might just mean that you have carbons colored orange.
[12:01 PM] rmoretti: Any final questions before we wrap up the office hour?
[12:01 PM] pc: thanks. We use sphere view to visualise shape complementarity. Just see that there is " Ligand Specific" color ^^ (it is more blue)
[12:02 PM] alcor29: Buon lavoro moretti. Thanks.
[12:02 PM] HuubR: Do you have any idea how long it is going to take to find the "Ideal Interface"? :-P
[12:02 PM] rmoretti: The "Ligand Specific" color can be changed from the View Ligand panel (as HuubR mentioned).
[12:03 PM] rmoretti: @HuubR "Ideal" is somewhat subjective. We're approaching this as a continuing process. (And only having the single interface to work on makes it much easier for us to implement those improvements.)
[12:06 PM] Vincera: IMAGE: http://fold.it/portal/files/chatimg/irc_142870_1637427980.png
[12:06 PM] HuubR: What I mean is, when can we expect the Original Interface to disappear in the Main release? In my mind, we're still a long way away from that.
[12:06 PM] Vincera: oops...
[12:06 PM] Vincera: unintended
[12:07 PM] pc: @rmoretti sometimes the visualization of tripple or single bond looks the same.
[12:08 PM] Vincera: Will we lose all of our recipes in the new release?
[12:09 PM] cjddig: (he/him): When will the new webpage come out? I've not heard about it recently.
[12:09 PM] rmoretti: @HuubR The current plan is to promote the current devprev to main once it's finished it's shakedown in devprev, likely sometime next week. (It's following the standard devprev->main migration process.)
[12:09 PM] HuubR: :-P
[12:10 PM] pc: I like the original interface ^^
[12:10 PM] HuubR: (that was my reaction to @cjddig:)
[12:11 PM] rmoretti: @Vincera There shouldn't be any issues with recipes with this release. Where the cookbook is might move around a bit, all your recipes should stay intact.
[12:11 PM] Vincera: D'accord.
[12:11 PM] Nicm25: is big deal, I need to teach others selection interface for migration...!
[12:12 PM] rmoretti: @cjddig: (he/him) The webpage update is proceeding apace. I'm not entirely sure what the timeline is, but we're getting closer.
[12:14 PM] HuubR: I have not tried the Intro Puzzles recently, but I saw that they have been adapted to the new interface. But maybe all those old time players are not very eager to go through all the Intro Puzzles?
[12:15 PM] rmoretti: @Nicm25 The tutorials (Campaign, Education puzzles, Dojo) have been updated for the new interface, and the hope is that they should function as a good introduction to things for people learning the interface. If you have suggestions on how to make them better (or new tutorials which teach things we may have missed), please let us know.
[12:16 PM] rmoretti: Thanks everyone for coming to the Office Hour. It was a pleasure chatting with you.

agcohn821's picture
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Groups: Foldit Staff
Office hours 12/21/21: led by beta_helix and sethcooper

8:57 AM] beta_helix: Hello everyone! Seth Cooper and I will start the last Office Hour of 2021 in a few minutes, but I wanted to share some reading material while you wait. Today's newspost previewing a new Foldit tool: https://fold.it/portal/node/2012556
Sneak Peak - The Trim Tool
Sneak Peak - The Trim Tool
[9:00 AM] Nicm25: hello!
[9:00 AM] beta_helix: Hello Hello!!
[9:02 AM] sethcooper: hello!
[9:02 AM] Josh: (he/him): hola
[9:03 AM] alcor29: Good morning.
[9:03 AM] beta_helix: Let's get the party started... does anyone have any questions they want to start off with?
[9:05 AM] beta_helix: (otherwise I'm happy to start with a question for Seth
[9:05 AM] Josh: (he/him): Okay, so a train leaves Berlin at 230 mph...
[9:05 AM] Nicm25: I'm interested about in the news article is whether it needs to be contiguous segment when trying out new interface WIP. if needs to be continuous, then we may have to think of it as domain proteins.
[9:05 AM] Josh: (he/him): Maybe it's too early for an office hour, west coast is still asleep
[9:06 AM] Josh: (he/him): I think it can be any selection, doesn't have to be contiguous
[9:06 AM] beta_helix: Nicm25 and alcor29 are awake
[9:06 AM] beta_helix: That is correct, it doesn't have to be contiguous.
[9:06 AM] Nicm25: it would be amazing if could be made into separate, detailed selection.
[9:07 AM] Josh: (he/him): I think --- but not sure --- if you select separate pieces, they will be joined by an open cutpoint
[9:07 AM] Josh: (he/him): or a constraint of some kind to show they are not connected
[9:08 AM] beta_helix: In the blogpost it selected a string of residues, but it also works with a sphere selection (for electron density, for example)
[9:09 AM] beta_helix: Question for Seth, can you tell us more about the new grid tool?
[9:09 AM] sethcooper: okay!
[9:10 AM] sethcooper: it essentially renders a grid along the x-y directions
[9:10 AM] sethcooper: with 1 angstrom cells
[9:10 AM] sethcooper: it centers itself where the camera's focus point is, so it's possible to move it around
[9:11 AM] sethcooper: e.g. if you put the mouse over a residue and press q the grid will move to that residue
[9:11 AM] sethcooper: maybe it could be useful for measuring distances or getting an idea of the scale of things
[9:12 AM] beta_helix: that might be particularly useful if we're able to load in much larger proteins in the future (with the new Trim tool)
[9:12 AM] sethcooper: it might also be more helpful if it's always perpendicular to the camera
[9:12 AM] sethcooper: instead of always x-y
[9:13 AM] beta_helix: Where can we find this new function, Seth?
[9:13 AM] sethcooper: in the view options!
[9:13 AM] Nicm25: "Show grid"
[9:14 AM] alcor29: Currently the grid moves with the protein. MIght be more useful it it was independent? (perpendicular)
[9:15 AM] alcor29: Translation is independent now.
[9:15 AM] beta_helix: I bet Seth is fixing that right now
[9:15 AM] alcor29: lol
[9:16 AM] sethcooper: i was looking at rotation of the grid
[9:16 AM] Nicm25: maybe ... : if fix it against the screen, can know it without changing conformation, just change camera angle orientation. (make it parallel to target between 2 points we want to know about)
[9:16 AM] sethcooper: (you do have to select "more view options")
[9:17 AM] jeff101: any news about Foldit's new web page or new tools for Electron Density puzzles?
[9:17 AM] beta_helix: Yes! jeff101!
[9:17 AM] alcor29: A problem we have in judging distances is that they appear different when we zoom around.
[9:17 AM] beta_helix: https://fold.it/portal/node/2012556
Sneak Peak - The Trim Tool
Sneak Peak - The Trim Tool
[9:18 AM] sethcooper: does the grid move with the protein now? it seems like when I move the protein the grid stays where it is
[9:18 AM] beta_helix: the Trim Tool was designed with ED in mind... but should be helpful for all puzzles
[9:18 AM] sethcooper: i mean, it rotates with the protein but not translates
[9:18 AM] sethcooper: i was looking in to fixing the rotation
[9:18 AM] robgee: +1 for the grid, thats handy.
[9:19 AM] alcor29: I like fixing rotation too. But others might have different preferences.
[9:19 AM] beta_helix: I don't want to give a specific date, but I believe the new website should be testable by the first week in January (Josh & Seth, does that sound right?)
[9:22 AM] sethcooper: partly i'd also prefer to not have a lot of extra grid view options since there are a lot already
[9:24 AM] beta_helix: and putting more options in the option.txt file isn't really a solution
[9:24 AM] Josh: (he/him): Sorry beta_helix, I have no new information on the website. Maybe @jflat06 can say more when he wakes up
[9:24 AM] beta_helix: I was just trying to remember from the last Foldit meeting
[9:25 AM] Josh: (he/him): I like that you think I pay attention in those
[9:26 AM] Susume: (she/her): I'd like to be able to fix the grid in space when there is a density, so I can see how I am rotating things relative to it (or don't use the grid for that, and add a set of 3 axes as a separate thing)
[9:26 AM] alcor29: Ditto.
[9:26 AM] jeff101: can we attach bands to points on the grid?
[9:27 AM] sethcooper: not currently but that's an interesting suggestion
[9:27 AM] Susume: (she/her): what a cool idea jeff101
[9:27 AM] beta_helix: then we can create lattices! ;-P
[9:28 AM] sethcooper: the grid isn't really full-fledged "object" in the game at this point
[9:28 AM] sethcooper: i guess it could be used a guide to place bands to space though
[9:29 AM] Nicm25: you mean, something that automatically implements z direction alignment to grid plane when the band is placed?
[9:31 AM] alcor29: A 3D fixed lattice?
[9:31 AM] sethcooper: i think it would be straightforward to add another checkbox for maybe grid fixed or moving
[9:31 AM] beta_helix: that's how protein structure prediction used to be done!
[9:34 AM] jeff101: are any new Foldit designs working in the lab?
[9:34 AM] beta_helix: @Susume: (she/her) and jeff101, did you see the new blogpost?
[9:34 AM] sethcooper: not sure if I can share a video
[9:35 AM] Susume: (she/her): the trim tool, yes I just read it - looks cool!
[9:35 AM] jeff101: I looked at the post about the Trim tool
[9:36 AM] Susume: (she/her): pls tell us more about it
[9:36 AM] jeff101: is there another post you want us to see?
[9:36 AM] sethcooper:
[9:37 AM] Susume: (she/her): cool, seth! that looks very different from the rotating grid
[9:39 AM] beta_helix: (I told you Seth was working on it during the chat )
[9:39 AM] Susume: (she/her): when it's stationary my brain says 'this is for measuring', and when it rotates my brain says 'this is for knowing where you are in space' - feels like two different tools at the moment, maybe at some point they will merge in my brain
[9:39 AM] beta_helix: that was the one I was referring to.
[9:40 AM] beta_helix: The new Trim Tool is work from our newest dev, apetrides, and came from our desire to make Electron Density puzzles easier to work with. Not only will this allow us to post large cryo-EM structures, but it should be useful in all Foldit puzzles (just like cutpoints)
[9:40 AM] Josh: (he/him): @beta_helix just a reminder, folks on the Foldit chat can't see Discord reply metadata, they just get the message.
[9:41 AM] Josh: (he/him): @jeff101 the blogpost beta_helix posted is the one he was referring to
[9:41 AM] beta_helix: thanks!
[9:41 AM] beta_helix: https://fold.it/portal/node/2012556
Sneak Peak - The Trim Tool
Sneak Peak - The Trim Tool
[9:43 AM] beta_helix: apetrides is just putting the finishing touches on it (we want to iron out as many bugs as we can find before letting you find more ) so you should be able to play around with the new Trim Tool soon in devprev (on a specific puzzle)
[9:43 AM] Nicm25: umm, I'm curious about behavior of recipes regarding hidden segments when using WIP, future scripting for ED puzzles.
[9:44 AM] Josh: (he/him): good question!
[9:44 AM] beta_helix: Yes... this is one element that apetrides is working on. Currently, saving/loading doesn't work after trimming.
[9:45 AM] Susume: (she/her): what is WIP?
[9:45 AM] Nicm25: I saw new trimming tool named 'WIP'.
[9:46 AM] beta_helix: Work in Progress
[9:46 AM] Susume: (she/her): oh ok, "work in progress", probably not the final name
[9:46 AM] beta_helix: Why Ih8 Proline
[9:46 AM] Susume: (she/her): lol
[9:47 AM] beta_helix: if beta helices weren't so cool, I probably would have picked an anti-proline username
[9:49 AM] beta_helix: So hopefully at the start of the new year we'll have the grid, this new Trim WIP Tool, and a new website for you to play with . Does anyone have any other questions that we can answer?
[9:51 AM] Nicm25: maybe we need tutorial as well, we'll look forward to it next month, but will there be more campaigns?
[9:51 AM] alcor29: Will the website already include recipe storage? Will cookbook be sortable and searchable?
[9:53 AM] Josh: (he/him): @Nicm25 I can't say much more right now, but next year there will be an entirely new Campaign and lots of new tutorials!
[9:53 AM] Josh: (he/him): @alcor29 I don't know about the cookbook GUI itself, but the website will have some new features for searching and sorting recipes, I think.
[9:54 AM] beta_helix: yes, it's designed to be much better than the current drupal site!
[9:54 AM] Nicm25: (rep) no problem, I just wanted to make an appointment for that text translation beforehand, thanks for answering.
[9:54 AM] alcor29: And will all.macro be stored on the web site?
[9:55 AM] Josh: (he/him): @alcor29 yes, I believe in the new website your recipe library will be stored on our servers and you can browse it on the website
[9:55 AM] Josh: (he/him): And all clients will sync with our servers
[9:55 AM] Josh: (he/him): So you don't have to worry about recipes being local to your machine any more
[9:56 AM] alcor29: Great.
[9:56 AM] jeff101: are Foldit's sponsors still enthusiastic about the project?
[9:56 AM] alcor29: Thanks seth, beta.
[9:58 AM] beta_helix: @jeff101 Yes! apetrides's work is funded by an NSF grant aimed at making it easier to fold into Electron Density... for players and scientists alike.
[9:59 AM] beta_helix: apetrides started in August, and our report is due next summer, so I am sure they will be very enthusiastic about the work so far (it's a 3 year grant)
[9:59 AM] jeff101: that's good.
[9:59 AM] beta_helix: Thank you all!
[10:00 AM] Nicm25: thanks all!
[10:00 AM] jeff101: yes,, thanks for having this office hour
[10:00 AM] Susume: (she/her): @beta_helix there was a recent article about photosynthesis proteins that listed several PDB structures with different kinds of problems - maybe we can help fix some of those
[10:00 AM] beta_helix: that is totally the plan, Susume:! (AJ is working on this too, as you know)
[10:00 AM] Susume: (she/her): yup, looking forward to it
[10:01 AM] beta_helix: Happy end of the year to you all, and we'll see you soon. Keep up the great folding!
[10:02 AM] sethcooper: thanks for the questions and comments everyone!
[10:02 AM] jeff101: :) Happy Holidays!
[10:02 AM] alcor29: Happy New Year all.
[10:02 AM] Susume: (she/her): thanks seth, beta, Josh!

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office hour 1/14/22- led by Horowsah

[1:30 PM] horowsah: Hi all- here for my office hour!
[1:31 PM] horowsah: I'm a general biochemist, so I'm good for lots of biochem questions
[1:31 PM] horowsah: That said, I'm not a protein design specialist, so can't guarantee my answers there
[1:31 PM] horowsah: I tend to work on ED puzzles and education mode mostly in Foldit
[1:31 PM] spvincent: Hi horowsah
[1:32 PM] horowsah: but in non-things, my lab works on how nucleic acids affect protein folding
[1:32 PM] HuubR: Hi @horowsah :-)
[1:33 PM] horowsah: howdy howdy
[1:33 PM] spvincent: It may be a bit early, but do you know if any of the recent ligand design puzzle solutions showed any promise?
[1:34 PM] horowsah: I don't know- haven't heard anything specific yet. I tend to get a bit of advanced warning but not always
[1:34 PM] HuubR: Do you know if there will be another Electron Density puzzle any time soon?
[1:35 PM] horowsah: hmm, it has been a gap hasn't it
[1:35 PM] horowsah: we've been saving up giving some to use with the Trim tool
[1:35 PM] horowsah: but we probably should do one soon since it has been awhile
[1:36 PM] HuubR: Last one I can find was Puzzle 2007, July 2021 :-o
[1:36 PM] horowsah: Yeah, def time to start getting another one in the works
[1:39 PM] HuubR: Is the Trim Tool ready for testing by us, regular folks? Or is that still too early?
[1:39 PM] horowsah: Last I saw, it had an issue still with disulfide bonds not working right, but in most other cases it seemed pretty much ready for a first iteration release.
[1:40 PM] horowsah: Ultimately, there will likely be a few releases of it where it gets enhanced
[1:40 PM] horowsah: but I would think we're close on the initial version, which should already be rather helpful
[1:40 PM] HuubR: Sounds interesting :-)
[1:41 PM] spvincent: Do any solutions to the HNet puzzles ever get synthesized?
[1:41 PM] horowsah: Sorry spvincent, I actually know very little about that process
[1:42 PM] spvincent: ok
[1:43 PM] HuubR: When you say "how nucleic acids affect protein folding", do you mean folding while the protein is still being assembled?
[1:43 PM] horowsah: yep
[1:44 PM] spvincent: Do you see any kind of role for in yourprotein/nucleic acid interaction work?
[1:44 PM] horowsah: Proteins are made as a linear chain of amino acids, and the folding process sometimes takes awhile so there's lots of opportunities for it to go wrong and so it needs help to get to the right fold
[1:45 PM] horowsah: I very much want to see the nucleic acid work in come to fruition, but first we need to improve how nucleic acids are handled in the game. Unfortunately, that might take quite some time.
[1:45 PM] horowsah: I should say some proteins fold on their own perfectly fine, but some need help
[1:46 PM] jeff101: How do they handle nucleic acids in eteRNA ?
[1:47 PM] horowsah: since they're 2d in eteRNA, they can use a much simpler algortihm than we use to handle 3D atomic-level info in Foldit. A lot of what we need is already embedded in the underlying code, but it hasn't really been unlocked or implemented yet.
[1:47 PM] jeff101: can we build nucleir acids with the ligand design tools?
[1:48 PM] horowsah: jeff101- that would certainly be fun to try, but I doubt it would work well. We can build nucleic acids in right now, but they are only so-so representations, and we lack tools to make them practical for players to manipulate
[1:49 PM] jeff101: is eteRNA useful even though it folds in 2d?
[1:50 PM] horowsah: so 2d representations of RNA are still really useful
[1:50 PM] horowsah: Often that's enough to be able to tell where an RNA is likely doing it's important stuff
[1:50 PM] jeff101: how? why?
[1:50 PM] horowsah: So in RNA, much more function can be interpreted from the secondary structure than in proteins
[1:51 PM] Nicm25: I never imagined future dealing with folding of hybrid proteins with RNA!
[1:51 PM] horowsah: A lot of that has to do with the way evolution has to keep RNA secondary structure intact for it to work
[1:52 PM] horowsah: Knowing the secondary structure of a protein is useful, but it tells you almost nothing about its function by itself
[1:52 PM] horowsah: With RNA, secondary structure tends to be more unique
[1:52 PM] Susume (she/her): (she/her): is there a good reference somewhere for how long proteins take to fold (by size, or by type, or whatever affects it)?
[1:52 PM] horowsah: Still, if you want to, say, design a drug that hits RNA, you still need 3D
[1:53 PM] HuubR: Forgive my ignorance, but is RNA a double helix, like DNA?
[1:53 PM] horowsah: @Susume (she/her): (she/her) I'm pretty sure this has been studied in detail, but I don't have a good reference off the top of my head. In general, multi-domain proteins fold much slower than single domain proteins. Even some single domain proteins, like some GFP variants, can take days to fold outside the cell.
[1:54 PM] horowsah: So RNA and DNA h form double helices, but RNA often forms much more complicated structures too
[1:54 PM] horowsah: They can even form knots
[1:54 PM] HuubR: :-o
[1:55 PM] HuubR: I've been wondering, if you have a helix and a sheet, what would work better for folding: helix at the N terminus, or sheet? In other words, does it help to have the center bit (that would be the helix) first, and then add the beta strands around it?
[1:55 PM] horowsah: I like to think of RNA as having double helix portions (the boring parts) and then parts that are constantly changing, and some that form crazy weird structures
[1:55 PM] jeff101: what are some common RNA 3d motifs (like Greek Key or 4-helix bundles or b-barrels in proteins)
[1:56 PM] horowsah: @HuubR That's a good question I don't know the answer to. Statistically, I assume that the N-terminus would favor one or the other, but I don't know which
[1:56 PM] horowsah: I bet someone out there has checked that out, not sure who
[1:56 PM] Josh (he/him): (he/him): HuubR, regarding RNA, you can maybe see from this link: RNA as two strands (double helix) doesn't need to always bond with its adjacent partner, which can make for some interesting bubbles and loops and things
[1:56 PM] Josh (he/him): (he/him):
[1:56 PM] horowsah: @jeff101 the basic building block in RNA is often called a stem-loop
[1:57 PM] Susume (she/her): (she/her): is the explosion in cryo-EM giving you access to more RNA-protein complex structures than what x-ray crystallography can do?
[1:57 PM] horowsah: ...but there's less definitive classification of RNA structures than for proteins
[1:57 PM] jeff101: is there a database for RNA similar to the SCOP database for proteins?
[1:58 PM] horowsah: @Susume (she/her): (she/her) I think so. It took awhile for cryo-em to catch up on RNA, and there are still some technical kinks being worked out, but pretty soon I expect it to help in a big way.
[1:59 PM] horowsah: @jeff101 I don't think there is a direct comparison for the SCOP database with RNA. I think in part it's that when we usually look at RNA structures, we look at small pieces of them at a time. It's not as easily modular as proteins are, but we have to study them that way because it's what we can do. In total, our knowledge of what whole RNAs look like when put together is still lacking
[2:00 PM] horowsah: I find how proteins and RNA bind each other fascinating, because it's typically a lot more loosey-goosey than how proteins bind each other
[2:00 PM] spvincent: eterna has some lab puzzles that aim to change the ribosome so as to enable it to synthesize things other than standard proteins. Concentrating on RNA naturally enough. But what about all the RNA/protein interactions? Will the ribosomal proteins have to be changed as well?
[2:00 PM] jeff101: how has DeepMind / AlphaFold affected your research?
[2:01 PM] horowsah: @spvincent In the ribosome, the RNA is usually more important, but I would think some engineering of h would help
[2:02 PM] horowsah: @jeff101 so far not in a huge way, but I expect that to change with some upcoming crystallography projects. With the RNA-protein interactions work it probably will soon as we start to try and come up with starting models of how they bind
[2:03 PM] HuubR: Does RNA always fold up the same way? (thanks for the interesting picture, Josh :-) If not, would that be a problem for Cryo-EM?
[2:03 PM] jeff101: like tRNA .. is it a pretty rigid structure?
[2:04 PM] horowsah: RNA and proteins h typically fold up the same way, but there are classes of h that don't and are intrinsically disordered. Some RNAs are quite rigid, but some switch between several different structures, which is a bit more common in RNA than in proteins. Those RNAs are sometimes very important biologically and are quite hard to study as a result of their switching
[2:06 PM] jeff101: is there such a thing as membrane RNA, where the hydrophobics are on the outside?
[2:07 PM] horowsah: That would be cool! Sadly, I've never heard of it before, and I think I would if it had been discovered. Some prokaryotes tether DNA to the membrane, though.
[2:07 PM] jeff101: do RNA complexes have a hydrophobic core and a hydrophilic exterior?
[2:08 PM] horowsah: Typically, the binding of RNA and proteins is mostly electrostatic (hydrophilic) in nature. Still, that's an overgeneralization, and often you see key hydrophobic contacts.
[2:09 PM] horowsah: There are proteins that can unwind RNA, and then sometimes you see the bases from the RNA stacking with aromatic hydrophobics from proteins
[2:10 PM] Susume (she/her): (she/her): @jeff101, there was a recent paper where they found that nucleic acids on the cell surface could be decorated with glycans (sugars), just like proteins and lipids can be decorated with glycans - so some RNAs do get expressed on the outside of cells (the other meaning of transmembrane - they cross the membrane, rather than sticking in the membrane)
[2:10 PM] jeff101: what about intracellular membranes?
[2:11 PM] jeff101: with only 4-5 RNA/DNA bluidling blocks, how do they make such diverse structures? are certain A T G C U considered hydrophilic or hydrophobic?
[2:12 PM] horowsah: So protein structural diversity is definitely greater than RNA. The thing that RNA has going for it here, though, is greater degrees of freedom within it. Basically, a rama map of an RNA shows it to be more flexible in the number of arrangements it can take compared with a protein of the same size
[2:13 PM] horowsah: on the intracellular membrane question, i'm not sure, I'd have to do some reading there
[2:15 PM] Nicm25: I've heard that we can create an arbitrary shape by creating like zipper with pair matching combinations of RNA bases... 'DNA origami'
[2:15 PM] horowsah: Yes, basically. DNA Origami
[2:16 PM] horowsah: it's pretty darn cool looking
[2:16 PM] spvincent: Wasn't there a game called Nanocrafter that tried to do something similar?
[2:17 PM] horowsah: yeah... not sure how it worked though
[2:17 PM] spvincent: I'm not sure if it still exists
[2:18 PM] HuubR: https://citizensciencegames.com/games/nanocrafter/
Citizen Science Games
Play Nanocrafter, use pieces of DNA to build everything !
Play Nanocrafer, a citizen science game, use pieces of DNA to build everything from computer circuits to nanoscale machine.
[2:19 PM] Josh (he/him): (he/him): scooper made that, I think! I doubt it's still playable
[2:20 PM] spvincent: there's a message on their website saying the project has ended
[2:22 PM] horowsah: yeah, that makes sense
[2:26 PM] Nicm25: in the future, I would like to see ability to load only some residues from solution sharing in ED puzzles to improve group work efficiency.
[2:26 PM] horowsah: That would be nice... we can put that on the list.
[2:27 PM] HuubR: Distributed Gaming? :-)
[2:27 PM] horowsah: we've talked about that a bit with in the past, but not sure if it really will happen
[2:28 PM] jeff101: I guess it'd be like the Trim Tool, but mutiple people can grab certain parts of the whle protein and work on them separately.
[2:28 PM] Nicm25: I came up with that idea because I didn't think huge protein could be processed by single computer
[2:28 PM] horowsah: yeah, pretty similar
[2:28 PM] jeff101: Later, soething puts all the parts back together.
[2:29 PM] jeff101: If several people work on the same piece, how to pick which persons' piece to put back into the whole protein?
[2:30 PM] horowsah: yeah that would be an interesting thing to figure out how that would work
[2:30 PM] horowsah: I have to go, thanks for the great chat all!
[2:30 PM] HuubR: Thank you, @horowsah!
[2:31 PM] Nicm25: thank you all.

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office hour 2/5/22: led by Sciren

[9:01 AM] sciren: (he/him): Hello Everyone! I hope you all are having a good day/night. It is a bit colder here than I'm used to, but I've got coffee to help
[9:01 AM] Dudit: (he/him): Hi @sciren
[9:02 AM] HuubR: Good morning @sciren
[9:02 AM] jeff101: Hi @sciren
[9:02 AM] Susume: (she/her): hi @sciren!
[9:03 AM] jeff101: @sciren what are you working on these days?
[9:03 AM] Susume: (she/her): pc and Huubr I love the idea of testing whether wiggle allows the ligand to enter the pocket when the opening is tight - @sciren, any comment on whether this experiment is real-world relevant?
[9:04 AM] sciren: (he/him): @jeff101 Currently I'm working on UI enchancments/bug fixes, along with adding improved features to help with the next round of Small Molecule Design Puzzles.
[9:05 AM] sciren: (he/him): @Susume I just want to make sure I understand. You want to leave the ligand outside the pocket and use wiggle to see if it will settle/dock into the pocket?
[9:06 AM] Dudit: (he/him): @sciren I think the time counter / time left until the puzzle expired is missing in the new Foldit user interface ( it's now hard to know when to submit to the scientist the last moment before the puzzle expired )
[9:07 AM] Susume: (she/her): yes, pc was using it with a rubber band to see if the small molecule could get inside, since the opening to the pocket in his protein is partly covered
[9:07 AM] sciren: (he/him): @Dudit The timer should appear when 24 hours are left on the puzzle. Is this happening for you?
[9:08 AM] pc: Hi. Yes we are interested at what happen in real life when ligand entering, to help us create better designs that work in lab ^^
[9:09 AM] pc: So we try to do a pseudo physic simulation ^^
[9:09 AM] sciren: (he/him): Interesting @Susume I will have to check to see how viable this would be. I don't believe wiggle is set up with this behavior in mind. There are other ways to make this happen in Rosetta, but I really like the ingenuity of forcing docking with the tools that you have. This is something I can look into further!
[9:10 AM] Dudit: (he/him): @sciren Thank you, the timer is appeared now
[9:11 AM] sciren: (he/him): No worries! @Dudit I was ready to jot it down as a bug just in case.
[9:12 AM] sciren: (he/him): @Susume this also brings up a good point, protein-ligand docking tools could be useful down the road.
[9:12 AM] pc: the new "neural net objective" is interesting. Do you plan to add score on it ?
[9:13 AM] HuubR: :-)
[9:13 AM] sciren: (he/him): @pc It is indeed really interesting! Unfortunately, I'm not sure about the progression plan for the neural net objective, but it is something I can ask about and let you know.
[9:15 AM] pc: Maybe scientist doesnt want we use too much AlphaFold for points. But a new AlphaFold request can be needed for points only if there is a mutation for exemple.
[9:15 AM] pc: (if there is points in "neural net objective I mean)
[9:16 AM] sciren: (he/him): As a gamer, I really like objective completion, but I also understand there are times when we want these objectives to be inherent in the scoring.
[9:17 AM] pc: I often share to scientist a lower score solution than my top score solution. Because the top score solution have often bad AlphaFold
[9:22 AM] pc: For binder puzzles, if I understand, scientists are mostly interested by interface(from player shared protein), and create new proteins with same interface (from library). Now with AlphaFold, maybe it is interesting to get more variants from players with moslty good AlphaFold similarity (and correct interface) ? (and not only the best protein with best interface)
[9:24 AM] Dudit: (he/him): @sciren: I think maybe there is a way to get an aggregate scoring system that is combining Rosetta & AlphaFold score into one whole score
[9:24 AM] pc: on the 32000 tested proteins , maybe we can add more proteins from players, to experiment how AlphaFold help ?
[9:24 AM] sciren: (he/him): @pc I'm not certain which is the best approach for this to be honest, but I it is something that I can pass along to get a bit more information about.
[9:25 AM] pc: thanks
[9:25 AM] HuubR: About bug fixing: I think georg137 had a very interesting suggestion in a feedback item last December (link below), to make a list available of bugs (and possibly suggestions) that have already been reported, and maybe also mentioning which ones are being worked on.
[9:25 AM] HuubR: https://fold.it/portal/node/2012568
[9:26 AM] HuubR: If such a list is accessible on the web site, it would be easier for us, players, to check whether a bug that we might encounter is already known or not, and possibly what its priorities are.
[9:28 AM] sciren: (he/him): @Dudit Before changing/adding to the existing scoring, we would have to make certain that it is the best approach. I'm sure there are pitfalls that we want to avoid before going down that path. But it is something to consider, and something I can bring up to the devs.
[9:28 AM] Dudit: (he/him): @sciren Thanks
[9:32 AM] pc: A suggestion for AlphaFold score, is to limit score after 80% confidentiality. I think maybe it can be enough.
[9:32 AM] sciren: (he/him): Absolutely, @HuubR feedback loop is a troublesome thing in any user facing project, and finding the best solution is tricky. It is something that we have discussed as a team, and we will do what we can to make sure we are addressing as many concerns as possible.
[9:32 AM] Vincera: May we please have the date/timer displayed during the full length of puzzle? As in blitz chess, eg. If I have 3-4 apparati set-up in workstation, I can walk from one to the other and on sight, see this notation. Should not have to incur further clicks; Multiple puzzles synchronously played with diff endtimes; we need constatnt display in the grey
[9:34 AM] HuubR: I agree with Vincera: what reason is there NOT to display it all the time?
[9:34 AM] Vincera: And some of ud devote device strictly to DEVPREV.
[9:35 AM] pc: When I use recipe with "wiggle + mutate + band" for exemple, score increase, but there is sometimes new buns after. Is there a solution or we can add a new slider "BUNS importance" ?
[9:35 AM] Vincera: Further, the time left when competing vs player in diff time zone will add to decision-making.
[9:37 AM] sciren: (he/him): @Vincera I will definitely note your suggestion. Understanding the broader use cases is extremely helpful in making these design choices.
[9:38 AM] Vincera: If I am up at 05h30 in my timezone to check the European stock market intime to make my trade for USA open, I can save this brain power for other part of the day/week. Thanx.
[9:39 AM] sciren: (he/him): @HuubR To answer your question, one of the design choices that was made was to attempt to declutter the existing Score Board which included the existing in puzzle timer. That being said, there should be a way to add this back in as an optional UI element for players who want to see it always displayed.
[9:41 AM] HuubR: Thanks. That brings up an interesting point: why do we have to set several options time and again when we start a client?
[9:43 AM] jeff101: Here is an old scoring suggestion: instead of counting non-ideal loops, count segments that are in non-ideal loops. Right now, there can be a non-ideal loop covering segments 11-30, and it gets less penalty than several non-ideal loops covering segments 11-14 18-19 and 27-29
[9:43 AM] HuubR: :-)
[9:43 AM] sciren: (he/him): Ah yes @HuubR . That is actually a bug that I am working on currently with @Josh: (he/him) . We were able to locate an issue that was causing the options to not save correctly. We're hoping to get that out the players as soon as possible.
[9:43 AM] Josh: (he/him): I have been summoned!
[9:43 AM] Josh: (he/him): Oh, the option saving bug, yes.
[9:44 AM] sciren: (he/him): Ha! With the power of your exceptional coding skills @Josh (he/him) himself has appeared!
[9:44 AM] Josh: (he/him): mostly with the power of pings
[9:44 AM] Josh: (he/him): currently virtually attending the Boston Festival of Indie Games
[9:45 AM] Josh: (he/him): someone here has nearly the same voice as you sciren: and it threw me for a loop for a second XD
[9:45 AM] jeff101: having the non-ideal loops penalty depend on the number of segments would help recipes gradually fix non-ideal loops
[9:46 AM] HuubR: Thank you, @sciren and @Josh. Looking forward to trying the next DevPrev release :-)
[9:46 AM] sciren: (he/him): @jeff101 I'm not sure about this scoring issue, but it is something that I can pass along to see what can be done.
[9:46 AM] Susume: (she/her): I like jeff101's idea about length of non-ideal loop being part of the penalty
[9:46 AM] sciren: (he/him): Alas, I am not in Boston at the moment. Though I would like to go some day!
[9:46 AM] jeff101: it seems to me that a non-ideal loop covering segments 1-7 should have less penalty than one covering segments 1-14
[9:47 AM] Susume: (she/her): that would also help with the situation where one resiude at the end of the protein is getting hit with ideal loop penalty - if length were taken into account, the penalty for a terminal resiude would at least be smaller
[9:47 AM] jeff101: right now, h count as 1 non-ideal loop, and recipes can't tell the difference just from the Foldit penalties
[9:49 AM] sciren: (he/him): I see what you are saying @Susume and @jeff101. Right now there is no distinction of total non-ideal loop segments.
[9:49 AM] HuubR: I would just hope that a bad loop at the end of the momomer in a Symmetry puzzle would not result in 2n+1 residues counting as bad loop. At the moment, that is the way such a situation is visualized :-o
[9:51 AM] jeff101: @HuubR is the n in 2n+1 residues the length of one monomer?
[9:51 AM] HuubR: Yes
[9:51 AM] Susume: (she/her): re: decluttering the GUI - to me it is only decluttered if I get some real estate back - having an enormous score number that takes up just as much space as the older more-informative panel is not less cluttered imo
[9:53 AM] Susume: (she/her): all the non-movable GUI elements feel very big on my screen, the devs must play at a higher res than I do
[9:54 AM] sciren: (he/him): Thank you @Susume You are correct. It is the same size as the old score panel. In this case the decluttering was in reference to how much information was being pushed into one panel. So the idea was to find the best homes possible for all of this information, because non of it is extraneous.
[9:55 AM] sciren: (he/him): Yes indeed, resolution differences are a challenge, and one that we are always trying to take into account, but unfortunately it doesn't always get adjusted the way we hope.
[9:56 AM] spvincent: Any chance of providing alternatives to the current colouring scheme? I think the saturated pastel look of a fully selected protein is perfectly hideous.
[9:57 AM] Vincera: Ditto that, spvincent. Puke factor.
[9:57 AM] Dudit: (he/him): @sciren Maybe resolution scaling in % ?
[9:58 AM] sciren: (he/him): I actually have been looking into color schemes a bit lately, and I will add selection as one of the elements to go along with that.
[9:58 AM] Josh: (he/him): it's Virtual this year!
[9:59 AM] jeff101: @Josh what is Virtual this year?
[10:00 AM] sciren: (he/him): @Dudit Indeed. That is something that has been discussed, and I think it will make its way in the future. Ideally, as many UI elements as possible would scale accordingly to screen size.
[10:00 AM] HuubR: Can we set the colours of selected residues in the file theme.txt? I see a ton of RGB values there, but it is not obvious what they represent.
[10:00 AM] Dudit: (he/him): @sciren Thank you
[10:01 AM] sciren: (he/him): @HuubR I'm not sure of the status of the theme.txt file and subsequent support. I believe it needs some updating.
[10:01 AM] HuubR: :-))
[10:01 AM] Josh: (he/him): this has some info: https://foldit.fandom.com/wiki/Theme
Foldit Wiki
The theme.txt file is used to customize your color scheme within Foldit. The file can be found inside the base Foldit directory (folder). To make a change, edit the values while Foldit is not running, otherwise your changes will be lost when the game exits.
[10:02 AM] Josh: (he/him): oh sorry @jeff101 I was responding to @sciren that the Boston Festival of Indie Games is virtual
[10:03 AM] spvincent: tx Josh: I'll take a look
[10:06 AM] jeff101: Thanks for having this Office Hour.
[10:06 AM] sciren: (he/him): Alright everyone, unfortunately I am going to have to go. I just wanted to thank all of you for your questions, and also take a moment to thank you for all of your feedback. As I have mentioned before, I am an avid gamer, and I know first hand how it can be to adjust to new user interfaces. Your comments and concerns have been and are extremely helpful in making sure provide you all with the best experience possible. So thank you again. I hope all of you have a wonderful day! Happy Folding!
[10:06 AM] Dudit: (he/him): Thank you so much @sciren & @Josh
[10:07 AM] Susume: (she/her): thanks @sciren!
[10:07 AM] HuubR: Thank you, @sciren and @Josh, and keep up the good work :-)
[10:07 AM] pc: thanks

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Office hour 2/27/22- led by bkoep

11:00 AM] bkoep: Hi all, welcome to Office Hours!
[11:00 AM] jmbrownlee333: hi
[11:00 AM] bkoep: I'll be here for the next hour or so to field questions and chat about
[11:01 AM] jmbrownlee333: I'll jump in. I have questions about the latest spate of ED puzzles. Comment on the usefulness of player solutions and also how are player solutions assessed in terms of the diffraction data?
[11:02 AM] bkoep: @jmbrownlee333, certainly! The recent ED Reconstruction puzzles are based on protein structures that are already published, but have some issues
[11:03 AM] jmbrownlee333: Issues? such as
[11:05 AM] bkoep: Usually these issues have to do with poor chemical geometry (unrealistic bond angles, etc.). These kinds of errors can result from over-fitting a model to questionable experimental data. These issues are more common in early crystal structures (pre-1990s, maybe), but they still sometimes crop up if the crystallographer or microscopist isn't careful
[11:07 AM] jmbrownlee333: so then model bias in the phases? The reason i ask is there were instances in 2108 where best-scoring conformations were at odds with the ED, in my solutions and my teammate’s.
[11:08 AM] bkoep: Sometimes it is difficult to fix these issues. Naively correcting the geometry can cause the "model-data agreement" to drop. The idea is that players can effectively reconcile differences between the model quality ( score) and experimental data (ED cloud)
[11:09 AM] bkoep: @JMbrownlee, yes there can be model bias in the phases that cause artifacts in the ED cloud—although we take some steps to limit model bias when we prepare ED puzzles
[11:10 AM] bkoep: in 2108 where best-scoring conformations were at odds with the ED, in my solutions and my teammate’s.
That is interesting! can you say more about this?
[11:11 AM] bkoep: Do you mean that there were parts of the ED cloud that were unoccupied by your best-scoring model?
[11:12 AM]alcor29: I get that mutating 20% of the residues will cause a significant jump in the confidence level. The question to us becomes which 20%. Sometimes NN paints a large portion of the mer as red. The permutations are daunting. Trial and error could work but very time consuming. Could the basic mutate programs read the NN data? Any other suggestions?
[11:12 AM] jmbrownlee333: For instance, lys 7 densiy was clearly heading towords an h-bond with the sulfate ligand. But any shaking or wiggling took the side chain out of the density.
[11:13 AM] jmbrownlee333: typing not my strongest skill ;)
[11:13 AM]alcor29: Sorry. Didn't mean to interrupt.
[11:14 AM] pc: @bkoep: Hi. Sometimes BUNS in a design puzzle, is a bit outside of the contact area.
Do you think that the water molecule is actually ejected ?
Maybe the protein can still bind more easily than if the BUNS was in the middle of the area ?
[11:14 AM] jmbrownlee333: and gln 69 loop had that side chain going in a different direction.
[11:17 AM] bkoep: lys 7 densiy was clearly heading towords an h-bond with the sulfate ligand. But any shaking or wiggling took the side chain out of the density.
Yes this is the type of thing that might cause problems, especially if the LYS requires a strained backbone or sidechain to make the H-bond. I don't know about this specific case, but if Wiggle has trouble it can mean the solution is stuck in a local minimum. For example, maybe an entire loop needs to be remodeled or Remixed so that the LYS backbone is better positioned to make the H-bond. You might have to sacrifice some ED fit in one area in order to make greater gains somewhere else.
[11:20 AM] jmbrownlee333: Last question on this. How will researchers use player solutions?
[11:20 AM] bkoep: @alcor29, yes that is the question! Even if the NN Objective tells you what region is bad, what mutations will fix things? Right now, you are sort of on your own to try different things. If there are problems with your original solution, it might be enlightening to look at the AlphaFold prediction. For example, if the AF prediction has buried a particular residue, you could try mutating that residue to something polar and charged—to "destabilize" the structure predicted by AlphaFold.
[11:22 AM] bkoep: In the longer term, we are working on a deep learning-based Mutate tool that may be more effective at improving AF confidence (possibly at the risk of a score decrease). Stay tuned for more developments in the coming months!
[11:24 AM] zippyc137: I had 83.7% confidence in AF with a design with 2 buns, solved the buns, got a higher score in , uploaded in AF again and got 73.7% confidence, I know buns are bad so this confuses me what score to follow
[11:24 AM] brunokestemont: Hi, I noticed that AF on monomer is'nt always a good indication of what will happen later on with symmetric. In symmetric, i usually mutate parts of the monomer (which gives something else), and the latest good scoring solutions perform better in AF as well.
[11:25 AM]alcor29: I think score decrease will be necessary, but that will apply to all so there would be no problem.
[11:27 AM] bkoep: @pc Yes, measuring BUNS can be a little unstable, due to approximations in our surface area calculations. This means that the BUNS Objective will occasionally flag an atom as buried even if water can technically get in and satisfy the atom. Unfortunately, if we want to remain responsive and (relatively) snappy, we have to make concessions like this.
[11:28 AM] pc: thanks
[11:29 AM] bkoep: I know some designers at the IPD do prioritize BUNS that are deeply buried (or "very buried" - VBUNS) over more marginal BUNS atoms ("surface buried" - SBUNS). I think that distinction may be a little too intensive for , but it is something we can consider in the future.
[11:30 AM] pc: @bkoep: In design puzzles, objective is to have more than 400 CS and less than -40 DDG.
But it is useful to share a solution with 350 cs and -30 ddg (but with no buns) ?
Is it interesting for scientists for other reasons than be selected for lab ?
[11:31 AM] brunokestemont: same question: is it interesting to share to scientists a 0 BUN solution (even with low HBonds) ?
[11:32 AM] bkoep: @JMbrownlee333 After ED Reconstruction puzzles, we do some further analysis with solutions to see how well they agree with the fundamental experimental data (i.e. we run crystallographic refinement with the models and evaluate R factors, Rama outliers, bond geometry, etc.). We hope to see that solutions improve the fit-to-data and geometry issues that were present in the published structure.
[11:33 AM] jmbrownlee333: Thx.
[11:37 AM] bkoep: @zippyc137 Yes, you are right! It is very confusing to get conflicting data from AlphaFold and the score and Objectives, etc. Unfortunately I don't have the answers to resolve your confusion. The team is working on new tools that will make it easier for players to try different things, but ultimately I think it's up to the player try and find something that works. Maybe we'll learn something from you!
[11:39 AM] zippyc137: thx, we"ll keep on experimenting:)
[11:40 AM] bkoep: @brunokestemont Yes, the AlphaFold confidence can be unpredictable. Sometimes a seemingly-innocuous mutation can cause a drastic change in confidence. Other times you can completely redesign your protein with hardly an effect on confidence. Unfortunately, the AlphaFold network is a bit of a mystery (this is an issue with deep neural nets in general), so we can't say exactly why AlphaFold "thinks" the way it does
[11:40 AM] brunokestemont: Now suppose I load an "original" from AF: I get the confidence noticed on screen. If I completely change the 3D structure without mutating anything, AF "score" will remain the same.
[11:41 AM] pc: zippyc137 : what I think (tell me if it is true) : big score in and low score in AF means : score for this specific folding is true, but this folding never appears in reality (or have less chances)
[11:43 AM] brunokestemont: AF rely on published data. Is there a risk of "autoreferencing" and repeating past errors ? (AF would not help us to "invent" original solutions)
[11:45 AM] bkoep: @pc Yes absolutely, please share "imperfect" solutions. If you've pushed a solution as far as it will go, and you just can't reach the Objective targets, then we'd like for you to share the solution and then move on to another attempt. The Objective targets are set at a "high bar" and we expect they will be difficult to satisfy.
[11:47 AM] zippyc137: @pc, I guess so too, so the scoring in should also change accordingly
[11:48 AM] bkoep: @brunokestemont Re: refolding the original - Yes, that's right. You can refold your solution all you like, but if you make no mutations then the AlphaFold prediction will stay the same.
[11:49 AM] alcor29: How have recent results from looked regarding NN / AF compliance vs scores and real foldability? Or is it too early to tell yet re NN usability?
[11:50 AM] pc: Is the AF prediction is precise ? Sometimes I try to create protein that keep a good similarity to have more chance to bind without deforming too much.
But I dont know if AF is enough precise for that.
[11:51 AM] alcor29: " but if you make no mutations then the AlphaFold prediction will stay the same." Doesn't this imply that AF is merely reading the string of AAs?
[11:52 AM] bkoep: @brunokestemont Re: autoreferencing - Good point, when evaluating a trained model (like AF) it is important to consider overfitting to the training data. However, the DeepMind team (and others) have shown pretty convincingly that AlphaFold is useful for extrapolating beyond the training data. I do not think we have to worry about AlphaFold showing bias against invented, original solutions
[11:52 AM] brunokestemont: In his video, nspc suggest to move the monomer away before to submit to AF. I'm not sure it's necessary. What do you advise?
[11:52 AM] Susume (she/her): yes, AF is only reading the string of AAs
[11:52 AM] pc: hum. I dont remember that
[11:53 AM] pc: but maybe I tested something else bruno
[11:53 AM] Susume (she/her): the similarity score reported by looks at your 3D structure - but AF and the confidence score do not
[11:53 AM] brunokestemont: https://www.youtube.com/watch?v=mrCuMu1ay_g
[11:54 AM] brunokestemont: ah ok thanks susume
[11:54 AM] pc: ah yes, it is the first base protein. I try to create a stable one with good AF before bind to target
[11:55 AM] alcor29: @Susume (she/her) Why does that seem a shocking revelation to me? So it's just saying this string is not in my library, Therefore it's not workable. But if that's so does it not imply then that our "creativity" is extremely limited, and that automation will work better?
[11:56 AM] Susume (she/her): it is not really saying 'not in my library' - it takes your string and makes a 3D prediction of how those AAs will fold - even if it has never seen that string before
[11:56 AM] bkoep: @alcor29 We don't have any data yet about how the Neural Net Objective affects wet lab results. It does seem like players overall are using the Neural Net Objective productively, to make solutions with improved AlphaFold confidence
[11:57 AM] alcor29: Re PCs procedure: I've had 85% stand alone and then 66% when adapted to symmetric chains.
[11:57 AM] pc: NN helped me fix some soluitons more easily. But it is hard when all is blue and confidence still at 75%. I have to see prediction for that.
[11:58 AM] pc: and continue fix
[11:58 AM] Susume (she/her): AF has been shown to be quite good at predicting the 3D shape for a novel designed string of AAs - and also of reporting low confidence for strings that are unlikely to fold well
[11:58 AM] alcor29: Ah thanks @Susume (she/her) .
[12:00 PM] bkoep: @pc Yes AlphaFold predicted structures are remarkably precise, and that is the main reason for all of the hype about it. In relation to other DNNs (like trRosetta), AlphaFold is actually no better at predicting design success vs. failure (will the design fold?). But, if the design does fold, then it probably folds just as the AlphaFold prediction says it will. Hopefully that makes sense?
[12:00 PM] ichwilldiesennamen: I've notice with symmetry-puzzles that when you have a good monomer with very good AF-values around the 90s then you can in most cases keep those values when attaching the copies. But you have to be careful not to mutate too much. A bit is alway s necessary (especially to get the HBnet)
[12:01 PM] pc: yes thanks. so my strategy can helps to have more successful binding maybe. I will try again sometimes ^^
[12:02 PM] brunokestemont: Me to I usually first design a very good monomer for bonus, AF and score. Then I try to bind or to make HBonds.
[12:03 PM] bkoep: @brunokestemont @pc It should not matter at all if you move the monomer away from the target before submitting to AlphaFold. Under the hood, completely removes the target before setting up the AlphaFold prediction. In fact, you are noticing that translating/rotating the monomer gives you different results, then we should treat that like a bug.
[12:04 PM] alcor29: We know how to make a monomer with 95%. Trick is to interface it to others. How good is AF at checking assemblages of mers?
[12:04 PM] pc: brunokestemont : yes, want I test with AF when I detach monomer is only create a first stable protein (but ignoring the target)
[12:05 PM]alcor29: Or is the question even applicable?
[12:06 PM] brunokestemont: @pc ok in order to avoid a target interfering with the monomer when trying to design a "perfect" monomer.
[12:07 PM] pc: yes ^^
[12:07 PM] ichwilldiesennamen: Shouldn't the best way to do the interface to the symmCopies be to have an as small as possible interface-area? Like this only very few SCs will have to be mutated (from hydrohpyl to hydrophob). And the AF-vaules will change only mildly.
[12:08 PM] brunokestemont: alcor29 I think that AF only test the monomer part, not helping for the interface
[12:08 PM] bkoep: @alcor29 Re: multimers - Great question! Yes, other researchers have found that AlphaFold is often capable of predicting multimer assemblies—although this is not currently enabled in puzzles. We may be able to add it at some point, but there are some problems we will need to iron out (for example, we would not be able to load AlphaFold multimer predictions into symmetry puzzles—what if the AF prediction is not symmetric?)
[12:10 PM]alcor29: Thanks very much bkoep:. It has been very useful
[12:10 PM] jmbrownlee333: Yes, thanks for giving up part of your Sunday
[12:10 PM] pc: thanks ^^
[12:11 PM]alcor29: @ichwilldiesennamen. Good idea. I will try it.
[12:13 PM] ichwilldiesennamen: @alcor29 Yes give it a try. I previously packed everything together as much aspossible but AF showed that this is not advisable. Now I try to have only 2 SCs as core-elements on the interface and build my HBnet with those. Works pretty well and AF stays up
[12:13 PM] bkoep: @ichwilldiesennamen Yes I like this approach of focusing on small interfaces in symmetric designs. The main difficulty to watch out for is that small interfaces may not have enough specificity. A lack of specificity may allow your protein to form off-target assemblies. Recall the infamous crystal structure of NinjaGreg's symmetric trimer design that folds into a tetramer: https://youtu.be/dxfE3A05rzA?t=190
Lab Report #22: Unexpected Lab Results
[12:15 PM] bkoep: Alright I will head out now. Thanks all for the questions and some great discussion about protein design!
[12:15 PM] bkoep: I'm looking forward to your latest designs. Don't forget to Share with Scientists!
[12:16 PM] ichwilldiesennamen: Thx bkoep: for your time!

agcohn821's picture
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Groups: Foldit Staff
Office hour 3/23/22- led by beta_helix

[10:01 AM] beta_helix: Hello everyone! Today's Foldit Office Hour will focus on discussing the new Electron Density Reconstruction puzzles!
[10:02 AM] jeff101: Hi beta_helix!
[10:02 AM] beta_helix: Hi jeff101!
[10:03 AM] beta_helix: How are things?
[10:03 AM] jmbrownlee333: Hi. So how are we doing?
[10:03 AM] beta_helix: Hi jmbrownlee333. All good on this side.
[10:03 AM] beta_helix: What have you thought of the recent ED Reconstruction puzzles?
[10:05 AM] jmbrownlee333: I took particular interest in RNase structure. The density and foldit score seemed to point in different directions in certain instances
[10:05 AM] beta_helix: So what did you do in that case?
[10:06 AM] jmbrownlee333: I sometimes wish for an fo-fc map.
[10:06 AM] beta_helix: Hahahahahhahahaa
[10:06 AM] jmbrownlee333: Since its a game i let score in foldit dictater what i do.
[10:06 AM] beta_helix: Funny you should mention that... as that is stage 2 of the ED grant we got from the NSF
[10:07 AM] jeff101: I follow the score too.
[10:07 AM] jeff101: what do you mean, stage 2?
[10:07 AM] beta_helix: It's tough because the density is supposed to be correct, but we know that there are artifacts
[10:07 AM] beta_helix: (sorry, the grant has different sections. The first part is the trim tool)
[10:08 AM] beta_helix: https://fold.it/portal/node/2012556
Sneak Peak - The Trim Tool
Sneak Peak - The Trim Tool
[10:08 AM] beta_helix: which should be out early next month (maybe in devprev even earlier)
[10:09 AM] jmbrownlee333: So how are we doing as a community. Have we impoved R and Rfree on our player solutions?
[10:09 AM] beta_helix: The other idea in the grant (stage 2) is to be able to allow you to refine your map based on your model
[10:09 AM] beta_helix: YES, you have!!!
[10:10 AM] jmbrownlee333: Is that the metric you are interested in?
[10:11 AM] beta_helix: This is only preliminary (hence no blogpost yet, as we need to run more puzzles) but most of your results have significantly improved over the starting PDB models (using multiple metrics).
[10:12 AM] beta_helix: For more details, these were the metrics we used in the Foldit "Determining crystal structures through
crowdsourcing and coursework" paper, (Figure 2): http://www.cis.umassd.edu/~fkhatib/Papers/NatureComm.pdf
[10:13 AM] jmbrownlee333: How have the puzzles been chosen for the latest ED puzzles?
[10:14 AM] jeff101: have they all used X-Ray Diffraction Data with the same resolution?
[10:14 AM] beta_helix: We've run 4 so far this year.
[10:16 AM] beta_helix: No jeff101, they have had different resolutions. We specifically picked a bunch of PDBs they did not seem great. It wouldn't be as useful as an initial test set to pick perfectly solved structures
[10:16 AM] beta_helix: How have you felt folding from a starting model, as opposed to previous ED puzzles that were most often giving as an extended chain?
[10:17 AM] jmbrownlee333: of course the starting model makes it so much easier.
[10:18 AM] beta_helix: What about the fun factor? Does it take away from the challenge, or on the contrary: it is less frustrating?
[10:19 AM] jeff101: I've had trouble finding specific features in the ED for these puzzles, but the starting structures seemed to be in good places, so my work has been lots of recipe-refinement.
[10:20 AM] Susume: (she/her): I only tried 2100 and 2108, starting from an extended chain because I'm stubborn like that - 1st went great, 2nd I could not solve from ext chain
[10:20 AM] jeff101: It's been nice to get a string of top-10 solos.
[10:20 AM] jeff101: These are pretty rare for me.
[10:21 AM] jmbrownlee333: It takes away from the challenge in a good way. It is sort of like the final steps in refinement, skipping the laborius chain tracing.
[10:21 AM] beta_helix: I guess it's nice that you can always start from an extended chain if you want to (or are too stubborn )
[10:21 AM] beta_helix: @jeff101 I always expected ED puzzles to require a lot more hand-folding. I'm glad you are still able to use recipes with the density. Do you find yourself hand-folding more at the end? Or not more than usual?
[10:22 AM] jmbrownlee333: I would say not more than usual.
[10:23 AM] beta_helix: Interesting... Susume:, I assume you do a lot of hand work (hard to run only scripts from an extended chain!)
[10:23 AM] jeff101: almost no hand-folding on my part
[10:24 AM] beta_helix: and into the top-10 with no hand-folding... that's awesome!
[10:26 AM] beta_helix: This is a random question, but if we had only given you an extended chain, but the AlphaFold button was on, would you all use that as a starting model?
[10:27 AM] jmbrownlee333: YAh!!
[10:27 AM] jeff101: I think I would too.
[10:28 AM] Susume: (she/her): yeah, on ext chain I do hand work until it is all placed, then scripts, then another round of hand work later if I have time- if starting from a given model, I start by walking the whole chain looking for places where I think I can improve it by hand - which is not fun unless there are some obvious places. If I can't find visible flaws, it's all scripts from there - not my favorite way to play, but many others are great at it, so keep 'em coming!
[10:30 AM] Susume: (she/her): not sure I would use the foldit AF as a start, since it doesn't have coevolution data - that's fine for designed proteins but not great for natural ones
[10:30 AM] beta_helix: Thanks! When you say: "walking the whole chain looking for places where I think I can improve it by hand" do you mean manually, residue by residue... or looking at the individual score of the backbone/sidechains?
[10:30 AM] jeff101: if you will have externded chain as initial structure, please at least give us the Blueprint Tool to use.
[10:31 AM] jmbrownlee333: I walk pretty much residue by residue.
[10:31 AM] beta_helix: Don't worry, jeff101... we don't plan on not providing the structures. The goal of this is to see if Foldit players can improve on models that have been deposited in the PDB.
[10:31 AM] Susume: (she/her): manually, by eye. if I had time to play a lot of these though I would try some scripts that help to look at subscores
[10:31 AM] beta_helix: Got it... now I see how that is not fun!
[10:32 AM] jmbrownlee333: could we have a tool thats color-by-density-score?
[10:33 AM] jeff101: yes please ... color by density score would be helpful
[10:33 AM] beta_helix: It would be pretty useful to be able to visually know which parts of the protein are not fitting well to density (we already can see those that don't fit at all)
[10:34 AM] beta_helix: I will bring your suggestion up at today's Foldit meeting
[10:34 AM] Susume: (she/her): are you going to check whether the areas that foldit players improve are the same ones that are flagged by the PDB's own quality metrics?
[10:36 AM] beta_helix: Yes indeed. In fact, there is already a website called PDBREDO that specifically focuses on improving the PDB. The cool thing is that, so far, the best Foldit models have been even better than PDBREDO!
[10:36 AM] beta_helix: We've already contacted the PDBREDO team and they seem interested in helping us out!
[10:38 AM] beta_helix: My student AJ (who you know, Susume) suggested: "Imagine if a scientist wanted to use a structure as a starting point for a new design problem, but they didn't really trust the PDB model on the RCSB website. How cool would it be if there was a "ask Foldit players for help" button, that would add it to the Foldit puzzle queue"
[10:39 AM] Susume: (she/her): I often look at the quality metrics on a PDB structure and think 'huh, ok, idk how to make use of that' - I'm glad they are there, but idk how to benefit from them. I LOVE AJ's idea!
[10:39 AM] beta_helix: It would kinda be the opposite of the "Share with Scientists" button
[10:39 AM] beta_helix: "Scientists asking YOU to share"
[10:39 AM] jeff101: the R and Rfree measures, what things within Foldit best reflect them?
[10:40 AM] Susume: (she/her): in Foldit land, scientists share with YOU!
[10:41 AM] beta_helix: @jeff101 Well, they represent the fit to density... so matching the density is important.
[10:41 AM] beta_helix: As I mentioned earlier, though, our long term plan (like... in 1-2 years) would be for Foldit players to recalculate the density based on your model and the phase information
[10:43 AM] beta_helix: essentially refining your density as often as you want, as you improve your model.
[10:43 AM] beta_helix: That's the idea, anyway
[10:43 AM] jeff101: would we be able to show our own latest version of the density while we work on a puzzle?
[10:43 AM] jeff101: like we calculate our own custom ED cloud?
[10:43 AM] beta_helix: You would be able to work with the density you more recently generated. Yes, exactly!
[10:44 AM] beta_helix: This is how crystallography programs do it.
[10:44 AM] beta_helix: They never come up with the perfect density and model on the first try.
[10:45 AM] beta_helix: Using the phase information, they generate density, refine a model into it, rephase, get a better map, etc.
[10:45 AM] jeff101: do you know of the ED clouds for these recent ED puzzles have been coarser than past ones? is it just me having trouble finding specific features?
[10:45 AM] petridecus: hi everyone, im andreas, the developer currently working on the trim tool for foldit! i can help answer any questions people have about it
[10:46 AM] Susume: (she/her): hi andreas! is this tool for trimming the density cloud?
[10:46 AM] beta_helix: This is why Foldit players have always impressed me with their ED work (when comparing to crystallographers). The expert in the paper I shared earlier was able to refine as much as they wanted... but Foldit players only had 1 map to work with!
[10:46 AM] petridecus: the trim tool is meant to reduce the active region of the protein that is being worked with @Susume: (she/her)
[10:47 AM] beta_helix: @jeff101 Yes, because these models are not great, the density hasn't been as high res as some of the previous ED puzzles
[10:47 AM] petridecus: you can use selection to isolate a certain region of a protein and then “trim” to work with that selection as if it were its own protein
[10:47 AM] beta_helix: https://fold.it/portal/node/2012556
Sneak Peak - The Trim Tool
Sneak Peak - The Trim Tool
[10:47 AM] beta_helix: (no density cloud there!)
[10:47 AM] petridecus: this will allow foldit to work with much larger proteins than before which could be especially helpful for ED puzzles
[10:48 AM] Susume: (she/her): oh ok cool!
[10:48 AM] jmbrownlee333: will we be able to control the slab depth more easily?
[10:50 AM] beta_helix: Andreas... how large a protein have you been able to run in Foldit without lag? (ie it almost feels like a 150-residue protein)
[10:50 AM] petridecus: with the trim tool you mean?
[10:51 AM] beta_helix: yes
[10:51 AM] petridecus: once you trim down to a region of N residues all puzzles effectively behave the same
[10:52 AM] petridecus: trimming and untrimming takes longer for super large proteins
[10:53 AM] beta_helix: @jmbrownlee333 can you describe "more easily"
[10:53 AM] Susume: (she/her): when you untrim, is there a cut at each end of your recent subset, where it connects back to the restored portion?
[10:53 AM] petridecus: yes, and in some cases there are a number of cuts
[10:54 AM] jmbrownlee333: I would kinda like a slider or dial to adjust slab width.
[10:54 AM] petridecus: also it’s worth noting that there will be an ensuing update where the “untrimmed” region i.e the residues beyond the selected region, will still be displayed (in a simplified fashion)
[10:55 AM] beta_helix: ...so you can still see where the rest of the protein is, but it doesn't kill your rendering
[10:55 AM] jmbrownlee333: I like that idea.
[10:56 AM] beta_helix: Once the Trim Tool is in devprev, and any initial bugs resolved, Andreas will hold an Office Hour for your feedback, before releasing it to main. Maybe even having it open in Foldit over Discord to talk about specifics...
[10:57 AM] beta_helix: Andreas... I said "early next month" for its release. Is that realistic?
[10:57 AM] petridecus: definitely
[10:57 AM] jeff101: in the recent handful of ED Puzzles, have the best-scoring solutions agreed with each other?
[10:57 AM] beta_helix: (We won't release it on April 1st where you can only Trim, and unTrim doesn't work )
[10:58 AM] jmbrownlee333: lol
[10:58 AM] beta_helix: Any last questions for us today?
[10:58 AM] jmbrownlee333: When can we expect a blog post about how players are doing on these puzzles?
[10:59 AM] beta_helix: Great question! Probably after we talk to the PDB REDO and RCSB teams... by then we'll have a bigger sample size as well.
[10:59 AM] jeff101: also, see my question about 2 minutes ago
[10:59 AM] beta_helix: Great job already on the ED puzzles... very exciting! Can't wait to see what you can do with Andreas' new tools!
[10:59 AM] beta_helix: Sorry Jeff, missed that one...
[11:00 AM] Susume: (she/her): the RCSB team are among my heroes - collaborating with them would be so cool
[11:00 AM] beta_helix: @jeff I believe the top solution has always been in the top5-10, but they have not all perfectly converged on the same topology
[11:00 AM] beta_helix: @Susume: (she/her) Right?!!
[11:01 AM] jeff101: thanks for having this office hour
[11:01 AM] beta_helix: Thank you all for stopping by today, especially on a weekday!
[11:02 AM] beta_helix: Thanks again and keep up the great folding!!!
[11:02 AM] beta_helix: Bye bye...
[11:02 AM] jeff101: bye

agcohn821's picture
User offline. Last seen 9 hours 20 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Office hour 4/23/22- led by jflat06

2:59 PM] jflat06: Hey everyone, I'll be around starting now for the office hours. I am a foldit developer with lots of experience with the code and a bit of biochemistry experience too.
[3:02 PM] Nicm25: hi! jflat06
[3:04 PM] jflat06: hello!
[3:15 PM] pc: hi
[3:15 PM] pc: what is the subject or kind of questions ?
[3:18 PM] pc: @jflat06 . Is it possible to have a buns detector tool in foldit, that is slower, but can detect without false positives (I mean not an objective but a separated tool) ?
[3:18 PM] jflat06: No specific subject, just as long as it's within my ballpark
[3:18 PM] jflat06: probably! I think we may even have such a thing
[3:19 PM] jflat06: It's always a big tradeoff between making things fast enough to be usable but still accurate enough to be useful
[3:19 PM] jflat06: We have a number of algorithms that people use internally in the lab for Rosetta that just aren't fast enough for foldit
[3:20 PM] pc: For me, AlphaFold is this kind of tool. a slow tool that make a protein Analysis. it is interesting to know if we are in a good or bad way
[3:21 PM] pc: as a developer to you watch "shared solution to scientists" ?
[3:22 PM] pc: @here office hours started
[3:23 PM] pc: what do you think about this suggestion : "A score modding for each objective". It can be usefull for buns for example. sometimes we need a different score penalty in each round phases.
[3:26 PM] pc: so "band recipes" or "mutate and wiggle recipes can be only to help "searching something" by trying multiple solutions. and "score modding" can be a setup that give player to goal to find. If we want less buns, if we want to increase surface..
[3:26 PM] jflat06: you mean additional options like "clashing importance"?
[3:27 PM] pc: yes, like the other under
[3:27 PM] pc: sidechain H-bond
[3:28 PM] pc: if I understand, a recipe think bonds give more points when it computes global score ?
[3:30 PM] pc: (with slider at higher value)
[3:31 PM] jeff101: I think the global score stays the same, but when you use tools like wiggle, they behave like the score being optimized has no clashing (for clashing importance of 0) or very strong hbonding (the hbond sliders set to 3)
[3:31 PM] jeff101: the global score shown to players stays the same
[3:31 PM] jflat06: the recipe uses the same score function as the one you see in the game, but it's possible for us to add additional sliders for various score terms. I think we have talked about this idea in meetings before, and it seemed like it wasn't quite as compelling as the case for clashing importance.
[3:32 PM] jflat06: but I think that's probably on a case-by-case basis for each score term, and it's possible that some of them might end up being very useful
[3:32 PM] jflat06: I can bring it up at our next meeting to get peoples' thoughts on it
[3:33 PM] alcor29: Hi jflat! 1. will the Graph Properties be restored so that my settings are saved? 2. Would it be possible to have a mutate program that can recognize that giving up a 600 point HBN for a 200 point segment is not a good idea, even for the integrity of the fold as well as for the global score?
[3:33 PM] pc: thanks
[3:34 PM] pc: yes, it can be usefull to have a easy control to what a recipe search, without modify script. (less buns, more surface, more ddg)
[3:35 PM] jflat06: 1. Can you clarify? 2. Mutate is supposed to do that, but it makes exceptions for if you have bands on your protein, or other situations where the score may technically need to go down.
[3:36 PM] pc: I mostly do hand folding, and recipes helps to find last optimisations. but it often not optimises what I want : with new buns score, now it add new buns each time I want to increase score with recipes.
[3:37 PM] jeff101: I have a question about puzzle 2137 (an ED puzzle). I am running it with clients from Oct 4 2021 to Jan 11 2022. I can save and share my solutions, but when I try to load my teammates' solutions, there is an error message and such solutions don't load. Did you guys change the internal file format for *ir_solution files recently so older clients cannot read ones made by newer clients?
[3:37 PM] jflat06: Internally, when you put bands on a model, the score function that the action is using is altered to include extra constraints. So it necessarily will lead to a decrease in foldit score, so we have to allow the score to drop in that case. However, this has collateral damage on things like your hbnet results.
[3:38 PM] jflat06: We have changed the solution file format recently, but it should be in a way that is fully compatible unless you have a very old client.
[3:38 PM] alcor29: Would this last change explain why it's harder to make and hold HBNs?
[3:39 PM] jflat06: I dont think so, though there some changes a few releases ago that modified the way these work, if i recall correctly
[3:41 PM] alcor29: @jflat06 Clarification of 1. On the old UIs i would set the number of undos that I wanted and the RAM and these settings were saved. Since the new UI these are not saved and I have to modify for every client I start.
[3:41 PM] jflat06: oooh, i see
[3:42 PM] jeff101: I think ichwill requested that hydrogen bond networks be calculated differently so more AA combinations could give 100% bonding
[3:42 PM] jflat06: that sounds like an issue for @Sciren (he/him) - I'd recommend making a feedback about it. We modified the ways settings are saved, and there's been some work trying to get everything updated to the new system.
[3:43 PM] jflat06: If you see anything like that, we can fix it, just let us know!
[3:45 PM] jeff101: @jflat06 what features have you been working on lately? what can you tell us about them?
[3:47 PM] alcor29: Maybe it's just me but lately it seems HBNs harder to achieve and hold. Will make a feedback for @Sciren (he/him) re graph properties.
[3:48 PM] jflat06: I've been helping with some exciting new features from bkoep, but I don't want to steal his thunder about it, so I'll just say that you guys are going to love it
[3:49 PM] pc: I suggested a new objective for binder puzzle that add penalty with solutions with too mush void in contact surface. But maybe it is better to have a better CS objective that take count about thoses voids.
[3:50 PM] jflat06: doing anything with voids is tricky, because our algorithm for detecting them isn't very good
[3:50 PM] jeff101: is covid still keeping most of the lab working remotely? are more people doing experiments in the lab these days?
[3:50 PM] jflat06: I think most people are actually back in the Baker Lab and doing experiments
[3:51 PM] jflat06: I actually work in the Comp Sci department, so I don't go into that lab other than for the occasional meeting
[3:51 PM] pc: "void resolution" looks to be important to have a successful binder protein.
[3:51 PM] jeff101: are the meetings more in-person these days?
[3:52 PM] jflat06: some of them have been, though we haven't been doing it as much recently.
[3:52 PM] jflat06: I don't think there's much in the way of covid restrictions affecting the lab anymore
[3:53 PM] jeff101: that's good
[3:53 PM] jflat06: re: voids - there's actually a much more accurate algorithm called dAlphaball
[3:53 PM] jflat06: but it's written in FORTRAN, if i recall correctly
[3:53 PM] pc: oh nice
[3:53 PM] pc: it can be good to have a more precise visualisation of them too ^^
[3:53 PM] jflat06: so it is difficult to integrate into Foldit, and it's slow...
[3:54 PM] alcor29: Having flashback to the 50s..........Fortran still around..
[3:54 PM] jeff101: how about the new Foldit web page? are you working on that? any estimate when it will go online? weeks? months? years?
[3:55 PM] pc: I try to pack my core inside my protein perfectly, or have a better contact interface, but i can't visualise all (I have only some red spheres sometimes).
[3:55 PM] jeff101: there are newer versions of fortran called fortran 77 and fortran 90
[3:55 PM] pc: thanks, can be interesting to have better void detection and visualisation ^^
[3:55 PM] alcor29: TX Jeff.
[3:56 PM] pc: of course a slow tool that is not an objective can be interesting too !
[3:56 PM] jflat06: The website should be coming 'soon' - it gets put on the backburner every time something more pressing comes up, like the work on Alphafold or some of these new tools that we have in the mix.
[3:57 PM] alcor29: I hope the new recipe listings will be easier to search, and will respond to words in the middle of the description.
[3:58 PM] jflat06: I believe we have that implemented! At the very least, making changes on the new site code is much easier than for the existing site, so feature requests like that are much more viable to implement.
[3:58 PM] Nicm25: For voids: it's enough to visualize them as densities in metapolygons just NOT the electron density as usual.
[3:59 PM] jeff101: @alcor29 if a recipe is already in your cookbook, you can look in the cookbooks all.macro file to search for special bits of code
[3:59 PM] alcor29: I mean the web listing not the client list.
[4:00 PM] jflat06: Yeah, the new web interface for recipes is more fully featured than the existing site, so hopefully you'll be pleased.
[4:01 PM] alcor29: @jeff101 Thanks. That's interesting. Though I once got into trouble by opening the all.macro file. Was advised never to open it.
[4:01 PM] jflat06: Well the all.macro file will be a thing of the past. Instead you'll have an extra 'recipes' directory that has a separate file for each recipe, all written in JSON
[4:01 PM] jflat06: should be a lot easier to work with
[4:02 PM] jeff101: I sometimes look at the all.macro file using Notepad or Wordpad. It is safe as long as I don't change it and then save it.
[4:02 PM] jeff101: When I am coding, I sometimes look for examples of how to use certain LUA commands by searching the all.macro file.
[4:02 PM] alcor29: Got it. Thanks jeff101
[4:04 PM] alcor29: Thanks @jflat06 . Appreciate it.
[4:05 PM] Nicm25: Thanks, new question to ask this, when editing recipe file do We need to calculate the verify? or do We need to define it in game as my own user?
[4:05 PM] jflat06: In the new system, you'll edit the files on the website, and then just click 'refresh' to load your changes into the game.
[4:06 PM] jflat06: There's also a button that lets you load a raw text file as a recipe, too
[4:06 PM] Nicm25: thanks for answering and thank you for today.
[4:07 PM] jflat06: No problem! I am going to go find some lunch now. Thanks for coming, everyone!
[4:07 PM] pc: thanks ^^
[4:07 PM] jeff101: thanks to you too jflat06


Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
Supported by: DARPA, NSF, NIH, HHMI, Amazon, Microsoft, Adobe, Boehringer Ingelheim, RosettaCommons