puzzle picture
1834: Coronavirus Anti-inflammatory Design: Round 3
Status: Closed

Summary

Name: 1834: Coronavirus Anti-inflammatory Design: Round 3
Status: Closed
Created: 05/06/2020
Points: 100
Expired: 05/13/2020 - 23:00
Difficulty: Intermediate
Description: Design an anti-inflammatory protein for COVID-19! The starting structure is a design by Bruno Kestemont from Puzzle 1824, as featured in our latest video Lab Report #8. Players may work to try and improve the starting structure, but also have the freedom to redesign binder from scratch. The best designs will have lots of helix or sheet structure, with a large core of orange hydrophobics. See our previous blog post for tips about designing a successful binder! Players may not load in solutions from previous puzzles.

Many COVID-19 complications are caused indirectly by the virus, and result from a severe over-stimulation of the human immune system. This kind of immune over-stimulation is commonly called a "cytokine storm." During a viral infection, immune cells normally release signaling proteins called cytokines, which inform the rest of the immune system about the infection and trigger inflammation. The inflammation is supposed to help the immune system fight off the infection, but too much inflammation can result in sepsis and organ failure.

One proposed strategy for treating serious COVID-19 cases is to prevent the "cytokine storm" by blocking certain cytokine signals. We want to design a protein that could block cytokine IL6, by binding to the IL6 receptor (IL6R). For more details, see our recent video update about blocking the cytokine storm.

In this puzzle, players are presented with the binding site of IL6R, which receives cytokine signals and triggers inflammation. The backbone and most of the sidechains are completely frozen, except for sidechains at the cytokine binding site. This puzzle also includes a binding helix fragment from the IL6 cytokine. Players can fold and design about 55 residues flanking the binding helix, with the goal of creating a well-folded protein that can bind the target in the same way as the IL6 cytokine. In order to bind the IL6R target, designs will need to make lots of contacts and H-bonds with the spike protein at this binding site. But designs will also need to have lots of secondary structure (helices or sheets) and a large core, so that they fold up correctly! See the puzzle comments for Objective details.
Categories: Design, Overall

Top Groups

RankGroupScorePoints
1Gargleblasters13,272100
2Beta Folders13,25684
3Go Science13,13370
4Marvin's bunch13,12458
5Anthropic Dreams13,12148

Top Evolvers

Top Soloists

RankPlayerGroupScorePoints
1Migi 71 82 Gargleblasters13,256100
2LociOiling 6 2 Beta Folders13,25399
3ichwilldiesennamen 166 141  13,24698
4actiasluna 27 22 Gargleblasters13,23297
5ucad 166 122  13,14896


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Comments

bkoep's picture
User offline. Last seen 7 hours 23 min ago. Offline
Joined: 11/15/2012
Groups: None
Objectives

Residue Count (max +275)
Penalizes extra residues inserted beyond the starting 152, at a cost of 55 points per residue. Players may use up to 157 residues in total.

Core Existence (max +1000)
Ensures that at least 25 percent of residues are buried in the core of the monomer unit.

Ideal Loops (max +500)
Penalizes any loop region that does not match one of the Building Blocks in the Blueprint tool. Use "Auto Structures" to see which regions of your protein count as loops.

SS Design (max +500)
Penalizes all CYS residues. Penalizes GLY, ALA residues in sheets. Penalizes GLY, ALA, SER, THR in helices.

HuubR's picture
User offline. Last seen 9 hours 17 min ago. Offline
Joined: 04/13/2020
Groups: Gargleblasters
Local versus global optimum

Thank you, bkoep, for (again) explaining the objectives that can give us bonus points. And thank you, and all of your fellow scientist working on this project, for your outstanding work!

Starting the puzzle with quite a high score is an interesting concept. I assume the reason why the initial score is so high, is because this protein was designed and folded by a very renowned player (see the puzzle description). Now the challenge to all of us is to improve that score.

In the (few) puzzles I played this far it was often not difficult to get the score well above the starting value by using a few simple actions, like apply and idealize secondary structure, shake, wiggle, but now all of that has already been done. I hope this does not scare off too many players, because it seems to be very hard to "get off the mark".

Starting at this high score might be a good way to encourage players to try different concepts for the secondary structure. In fact, that is what I did initially. I have a habit (in puzzles as well as in real life) of not always going with the crowd. Although I acknowledge that teamwork can be very powerful, I sometimes feel that there are already enough pairs of eyes looking at something from the same viewpoint, and then I tend to try a different perspective. There was an interesting discussion in global chat yesterday about teamwork, and about working in a local optimum versus trying to find the global optimum. I think it was LociOilingIRC who raised that point.

Having said all that, can I ask you, bkoep, or one of the other scientists, a question?

I wonder whether the score that we get in this puzzle is a good indication of how well a certain protein will stick to the binding site. Correct me if I'm wrong, but isn't most of this score made up of how well the protein itself was built up and folded?

What I tried is the following. Starting from the initial design (reset the puzzle), I moved the protein away from the binding site, and then tried to find a new (local) optimum by shaking and wiggling. In my mind, the number of points that you lose this way (or in other words, the number of points gained by placing the protein at the binding site and re-optimizing it there) would be an indication of how "sticky" the protein is. Again, please correct me if I'm wrong. I am not a molecular biologist, just an electrical engineer who likes puzzles.

Could you give us an idea why the score (and bonus points) were set up the way they are? Thanks!

HuubR's picture
User offline. Last seen 9 hours 17 min ago. Offline
Joined: 04/13/2020
Groups: Gargleblasters
The answer was already there...

Looks like you had already answered my question, long before I asked it, in your blog post Analysis of protein binder designs. Thanks! Lots of interesting stuff in there, way more than I could ask for.

This gives me enough incentive to stop focussing on the score and go my own way. Don't know whether it will get us anywhere, but the least I can do is try.

Now there's only one question left: if I would indeed find a "sticky" protein, but with a Foldit score that is lower than most other players', how can I make sure that this design is noticed by you, the scientists? Should I just save a solution and "Upload For Scientists" (in the Open/Share Solutions dialog box)?

bkoep's picture
User offline. Last seen 7 hours 23 min ago. Offline
Joined: 11/15/2012
Groups: None
Upload for Scientists

Yes! That's exactly what the Upload for Scientists button is for. If you think your solution is promising, but it doesn't make the leaderboards, use Upload for Scientists and we'll be sure to take a look.

Great questions, glad you were able to find our previous blog post!

Mikisp's picture
User offline. Last seen 42 min 52 sec ago. Offline
Joined: 04/01/2020
Groups: None
SS?

LHHHHHHHHHHHHHHHLLLLLEEEEEELLLLLLHHHHHHHHHHHHHHHLLLLLEEEEEEL

LociOiling's picture
User offline. Last seen 3 hours 10 min ago. Offline
Joined: 12/27/2012
Groups: Beta Folders
that's the secondary structure...

Not sure if that was a question, but that's the secondary structure for each segment, using the codes:

  • L - loop
  • H - helix
  • E - sheet

The recipe print protein and several others use this format.

Actual science tools like JPred use a similar format, but with "-" instead of "L" to indicate loop.

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