Developer Chat

inkycatz Hi everybody! Welcome to our scheduled Science Chat! As you all probably are aware, chats are logged, so if you have to go don’t worry we post the log afterwards. :) 14:59
inkycatz I know a bunch of you had to go to sleep, so dream well, read later. :D 15:00
inkycatz As you know, question priority goes to those who posted ahead of time. Thank you all this month for your super enthusiastic participation on that front. 15:00
inkycatz As a side note, I wrote a little post and added it in the forum about “asking great chat questions” for future use, and put it here: 15:00
inkycatz http://fold.it/portal/node/997632#comment-32516 15:00
inkycatz Read, enjoy, ask me questions 15:00
inkycatz BTW, there were a number of questions on the following topics that we’re thinking may be better short posts or blogs to fully talk about things on a level that you all would appreciate vs those “speedy y/n answers” during chat. So look for possible upcoming blogs over the next few months or so on these topics: 15:00
bkoep Hi, everyone! 15:01
free_radical hi 15:01
inkycatz (also wanna give a hi to our scientists sitting in today of course!) 15:01
inkycatz I see bkoep, free_radical, horowsah 15:01
Scopper Hi :) 15:01
horowsah howdy, y'all 15:01
inkycatz Just a quick note on the future blog topics before we get on to team updates :) 15:02
inkycatz This stuff would take up so much time, blogs are cooler: 15:02
inkycatz data collection and storage (what gets stored, and how we use it) 15:02
inkycatz research questions we’re addressing with the data on player moves 15:02
inkycatz priorities, what are they, how are they selected 15:02
inkycatz personal goals and science dreams from the team 15:02
inkycatz So let’s roll with some updates. free_radical, any news for us? comments on the experimental client? 15:02
free_radical I first want to thank everyone for helping test the experimental design 15:03
free_radical I know that it can be extremely frustrating playing the game and having it crash 15:03
free_radical I have been taking time to read all your comments and address them as best as I can. I think the end product is going to be great 15:03
free_radical and there is going to be a lot of cool science done with the new tools 15:03
free_radical In a future blog post, I will discuss the targets that we would like to look at for drug design 15:04
free_radical and will ask everyone to put their comments on what they would like to target, out of a prepared list 15:04
free_radical We will be follow those targets and try to synthesize the drugs that everyone makes 15:05
free_radical as well as get experimental results that show whether the designs work or not 15:05
free_radical its going to be pretty awesome :) 15:05
free_radical there will be a future blog post with new udpated tools and more filters. Also, I will give a more detailed explanation of the tools and how to use the filters 15:06
free_radical thats all I have 15:06
inkycatz How about you, bkoep? 15:06
inkycatz (We can of course, dive right on into the questions if you want.) 15:08
bkoep I don't think I have any general updates to give. We've been happy with the results from recent design puzzles, and I think we have some relevant questions queued up about the Rama Map and Ideal Loops... 15:08
inkycatz We do! 15:08
inkycatz Let’s grab those questions. 15:08
inkycatz Regarding the "Center/Align Protein to Density” button in Electron Density Puzzles, can you give out details about how this button works at present? 15:08
inkycatz (Rama stuff’s next, I promise, folks) 15:08
bkoep If jflat06 is around, he'll probably know more about the technical implementation... 15:09
bkoep But essentially, the "Center/Align Protein to Density" button is simply meant to translate the protein's center-of-mass to the center of the density map. 15:10
inkycatz How do the design puzzle solutions look since Rama map came out? What suggestions would you give us to help given the current tools? 15:10
bkoep There is no fancy atomic-resolution fitting to properly rotate or translate the protein 15:10
bkoep About the Rama Map... 15:11
bkoep I'm very pleased that players have been using the Rama map! 15:11
bkoep It does seem that players are incorporating more of the Ideal Loops into their designs, which is even more exciting! We can be much more confident that these loops will fold properly in a designed protein. 15:11
bkoep And we have seen a few recent Foldit designs that look promising (hopefully we’ll have more details to share soon…). 15:12
bkoep I don't know if I have any specific suggestions about how to use the tools more effectively. 15:12
spvincent in the absence of any feedback on designs it's very hard to know if we're on the right track 15:13
bkoep @spvincent, that's understandable, and hopefully I can write up a detailed blog post soon with some specific results 15:13
spvincent tx 15:13
inkycatz Now that we’ve been working with the Rama map for a bit, what plans are underway to help improve results? 15:13
bkoep In general, I am really curious to see if Foldit players can make designs in which ALL loops are Ideal Loops. 15:13
bkoep A few players have managed to make such designs, and these tend to be the more promising—even if they aren't the best-scoring. 15:14
bkoep We may try out a filter that gives a penalty for non-ideal loops, to see if we can "boost" the scores of those ideal designs 15:16
spvincent Isn't that the job of the Ideality component of the scoring function? 15:17
bkoep Also, there have been a lot of great suggestions in the Feedback forums for improvements to the Rama Map tool. 15:17
bkoep We’re working on implementing as many of those as we can. I hope that will make the Rama Map even more useful! 15:17
inkycatz :) 15:17
bkoep @spvincent, unfortunately, no 15:17
inkycatz One more Rama question then! 15:17
inkycatz Currently, all of the ideal sheet-sheet loops provided with the Rama map turn the same way. Does the team have access to any 4-residue sheet-sheet loop that turn the other way, and if so, can we expect to see some of those as well in the near future? 15:18
bkoep The term "ideal" has been overloaded in Foldit, and means different things in different contexts... 15:18
bkoep I know this is terribly ambiguous and leads to a lot of confusion—maybe we'll be able to address this soon 15:19
bkoep The "Ideality" score component addresses bond geometry (i.e. the lengths and angles of chemical bonds) and is informed by quantum mechanics calculations. The "Ideality" score in Foldit is a big problem at cutpoints, where we try to create a bond between two atoms that may not be properly positioned. 15:20
bkoep The "Ideal Loops" come from a Baker lab study in which certain loop shapes were found to be over-represented in known structures. It was found that these loops can be incorporated into designs to successfully produce "ideal protein structures" of many different topologies. 15:22
bkoep http://www.ncbi.nlm.nih.gov/pubmed/23135467 15:23
bkoep Back to the Rama Map question... 15:23
bkoep This is an astute observation—since loops are directional (e.g. from N-terminus to C-terminus), hairpin loops have a "handedness" to them 15:24
spvincent i've seen the paper: still I thought the possibility that FoldIt players might come up with novel folds that nature doesn't have much use for was part of the point 15:25
bkoep Most of the hairpin (sheet-sheet) loops shown in the Rama Map are "left-handed" 15:25
bkoep There are a few Ideal Loops that are "right-handed", but these are less frequently observed and are not shown in the Rama Map. 15:26
bkoep However, there is a way around this... 15:27
bkoep If you have two neighboring strands and you need a "right-handed" loop to connect them, you can extend each strand with one residue to make the connection "left-handed" (since the orientation of the strand flips with each residue) 15:29
bkoep We may also extend the gallery of Ideal Loops in the Rama Map, so that they include additional (but less frequent) loops 15:30
bkoep @spvincent, yes, and that is still very important to us 15:30
inkycatz So let’s keep on with the posted questions :) 15:31
inkycatz As we do have still a bunch of them. 15:31
inkycatz What kind of issues are currently present in allowing Citizen Scientists to invest in research on or around Foldit? What are the current policies the team has about this sort of activity? 15:31
free_radical The main issue is IRB and how it effects the players and those participating 15:32
bkoep However, we have had a tough time figuring out why Foldit designs don't look as good as Baker lab designs. Hopefully, we can experiment with Foldit designs that also subscribe to the Ideal Loops rules, and that will tell us if that is the main issue. 15:32
bkoep I am afraid that an Ideal Loops filter will be too restrictive for Foldit players' creativity, so hopefully it will prove unnecessary 15:33
free_radical *sorry, didnt mean to intterupt 15:34
inkycatz it’s okay free_radical! That’s a pretty good answer for part of it :) 15:35
bkoep Ah, I'm finished (thanks for your question, @spvincent) 15:35
free_radical IRB governs what we are allowed to do with players data 15:36
free_radical for players who want to contribute to Foldit-outside of playing- it becomes complicated 15:36
free_radical even contributing to the base source code can be a problem, because thats where we keep information on how the chat servers are ran, how code and scores are distributed, etc 15:37
free_radical that being said, we are open to suggestions on what can be contributed 15:37
inkycatz (note, open in a contact us way, not *now*) 15:37
inkycatz Let’s go to our next question. When posting a protein with contact map (or other de novo), do you have any prior idea on which kind of design it could be? If so, are there advantages to not providing this information for the community? 15:38
inkycatz unless you guys had more on that 15:38
free_radical I would suggest opening a forum post on what people would like to contribute and we can have a dialoug on it :) 15:39
inkycatz I love that idea 15:39
free_radical theres a lot of awesome science to be done and Foldit has a track record of getting it done :) 15:40
bkoep First, I don't think we've run any Contact Map puzzles with designed proteins. We usually derive predicted contacts from evolutionary data (and of course, there is no evolutionary data for designed proteins). 15:40
bkoep Usually, the only way we can infer the fold of a protein is if we can establish a homologue, and most de-novo Foldit puzzles target proteins without any known homologues 15:42
bkoep In those cases, the best data we have about the protein's fold is the contact map itself, and we'd rather provide that data directly to Foldit players. 15:43
bkoep By "those cases," I mean "cases without known homologues" 15:43
inkycatz Kinda related: What is the source of the recent de novo puzzles? 15:44
bkoep Recent de-novo puzzles have been a mixed bag of Foldit player designs (we're curious if players can more easily predict the structure of player designs) and native proteins which have a structure pending publication, or otherwise have some interesting data like predicted contacts 15:47
inkycatz And then we have this question: How do you study designed proteins? 15:48
bkoep We've had a couple of blog posts about the types of analysis we do with designed proteins... 15:50
bkoep https://fold.it/portal/node/997313 15:50
bkoep http://fold.it/portal/node/998024 15:50
bkoep Essentially, we run some additional computational analysis, and a select few are developed in the wet lab for experimental testing 15:51
spvincent knowing which ones they are would be motivating 15:53
inkycatz Duly noted, spvincent. 15:53
inkycatz That’s all the questions we figured we’d have time for today, but if the team has any parting comments, or wants to stick around for more, it’s up to them. :) 15:55
inkycatz I do want to thank bkoep and free_radical, as always, insightful stuff 15:55
inkycatz remember if your question wasn’t answered from the thread today, it may be coming up in a future blog post 15:55
jeff101 yes, thank you all 15:55
inkycatz or a future chat :) 15:55
free_radical you can catch me with the discord app @free_radical 15:56
inkycatz thank you all for coming, and for all the great questions in the thread - truly the community comes through every time :D 15:56
inkycatz our next official chat will be in July! 15:56
inkycatz Our log will be posted soon, courtesy of jflat’s help (so thanks there). 15:56
inkycatz And everyone who dozed off can catch up on what they missed. :) 15:57

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