Hi Foldit players! Here are the Office Hours transcripts: They begin with the first one but you can find the latest one HERE
[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...
[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!
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
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
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!
[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
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
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!
[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!
[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
[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!
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)
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
[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...
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...
[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
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:
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:
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
[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
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:
[6:15 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!
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!
[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
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.
[3:10 PM] formula350: What about using WebGL or CL instead of JS? (which seems to run smoother than JS anyhow)
[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.
[3:25 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!
[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 ^^
[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!