puzzle picture
1824: Coronavirus Anti-inflammatory Design
Status: Closed

Summary

Name: 1824: Coronavirus Anti-inflammatory Design
Status: Closed
Created: 04/10/2020
Points: 100
Expired: 04/17/2020 - 23:00
Difficulty: Intermediate
Description: Design an anti-inflammatory protein for COVID-19! 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).

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. Players can design a new protein that binds to these sidechains, blocking interactions with the 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
1Gargleblasters13,163100
2Go Science13,14286
3Beta Folders12,81874
4Anthropic Dreams12,75763
5Void Crushers12,74753

Top Evolvers

Top Soloists

RankPlayerGroupScorePoints
1actiasluna 27 18 Gargleblasters12,885100
2johnmitch 149 16  12,820100
3LociOiling 7 1 Beta Folders12,81899
4Crossed Sticks 149 64  12,80798
5ZeroLeak7 32 6 Go Science12,75897


Need this puzzle? Log in to download.  

Comments

bkoep's picture
User offline. Last seen 13 hours 17 min ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Objectives

Residue Count (max +550 +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.

RockOn's picture
User offline. Last seen 13 hours 50 min ago. Offline
Joined: 06/01/2011
Groups: Go Science
Res 92 = A cysteine floating alone

Are we to bind with a cys bridge?

bkoep's picture
User offline. Last seen 13 hours 17 min ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Lone cysteine disulfide

Yes, the target protein is a bit peculiar this way—a residue near the binding site makes a disulfide with a lone cysteine.

Note that the lone cysteine still has backbone polar atoms that may need to make hydrogen bonds if buried away from the surrounding water! (Try the Sticks view option and CPK coloring to see these more clearly.)

NinjaGreg's picture
User offline. Last seen 10 hours 55 min ago. Offline
Joined: 05/21/2010
Groups: Go Science
Since you mention the

Since you mention the backbone polar atoms, should we assume that the cysteine is actually connected to something, so we should try to put part of our protein too near that point in space?

bkoep's picture
User offline. Last seen 13 hours 17 min ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Lone cysteine

No, CYS 92 is not connected to anything except CYS 46 (by a disulfide bond).

Even though the CYS 92 backbone is not connected to other amino acids, it still has polar atoms. If these atoms are buried away from surrounding water, then your design should make H-bonds to those polar atoms.

It's not necessary for your design to interact with CYS 92. But since it is so close to the binding site, we expect that many designs will interact with it (and that's okay!).

jeff101's picture
User offline. Last seen 16 hours 37 min ago. Offline
Joined: 04/20/2012
Groups: Go Science
Must we form a disulfide bond between cys92 and our binder?

Are we supposed to form a disulfide bond between
cys92 on the target protein and one of the residues
on our binding protein?

bkoep's picture
User offline. Last seen 13 hours 17 min ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
No need to form disulfides

CYS 92 is already connected to CYS 46 by a disulfide bond, so it cannot participate in a disulfide bond with your binding protein.

jeff101's picture
User offline. Last seen 16 hours 37 min ago. Offline
Joined: 04/20/2012
Groups: Go Science
Should we leave voids near cys92?

Are we supposed to leave the space around cys92 empty,
or should we try to fill that space with parts of our
binding protein?

bkoep's picture
User offline. Last seen 13 hours 17 min ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
No voids

No, there's no need to leave empty space around CYS 92. You can fill that space with your binding protein. (But make sure to make hydrogen bonds if you bury any polar atoms!)

RockOn's picture
User offline. Last seen 13 hours 50 min ago. Offline
Joined: 06/01/2011
Groups: Go Science
7 invalid residues are scoring against us?

They are all out of our control.

bkoep's picture
User offline. Last seen 13 hours 17 min ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Apologies

Yes, we had trouble configuring the Objective to ignore those residues. We may be able to fix it in future puzzles. Sorry for the inconvenience!

HMK's picture
User offline. Last seen 18 hours 7 min ago. Offline
Joined: 05/14/2015
Groups: SETI.Germany
Number of fragments?

Sorry, I am rather a rookie here and I don't understand one thing with this puzzle:
Does the fixed part of the puzzle consist of several peptide fragments? There seem to be gaps in the backbone.

Kind regards
Matt

bkoep's picture
User offline. Last seen 13 hours 17 min ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Fragmented target

Yes, good observation! We're using a truncated model of the target, to help with software performance.

The target protein IL6R is much larger than what is shown in this puzzle (>200 residues). We could include those other residues in Foldit, but then we would have to score and render another 150 residues, which can cause lagging tools and choppy graphics. Since those extra residues don't participate in binding, we can omit them from the puzzle without affecting the scientific validity of the challenge.

To see a more complete model of the target (and how it binds the IL6 cytokine), see the PDB entry1P9M.

HMK's picture
User offline. Last seen 18 hours 7 min ago. Offline
Joined: 05/14/2015
Groups: SETI.Germany
Thank you very much for the

Thank you very much for the explanation and the information given.

Joined: 07/31/2008
Groups: None
Wrong highlights for SS Design objective

Showing the contradictions to this objective highlights areas on the IL6R. Showing the non-ideal loops (even though all were created originally with blueprint tool) shows both ends of the designed protein. The loop to nowhere.

Download links:
  Windows    OSX    Linux  
Windows
(7/8/10)
OSX
(10.12 or later)
Linux
(64-bit)

Are you new to Foldit? Click here.

Are you a student? Click here.

Are you an educator? Click here.
Social Media


Other Games: Mozak
Search
Only search fold.it
Recommend Foldit
User login
Topics
Top New Users
Sitemap

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