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1828: Coronavirus Anti-inflammatory Design: Round 2
Status: Closed


Name: 1828: Coronavirus Anti-inflammatory Design: Round 2
Status: Closed
Created: 04/22/2020
Points: 0
Expired: 04/29/2020 - 23:00
Difficulty: Intermediate
Description: Note: This puzzle was closed early due to some problems with the protein backbone, and a corrected version was reposted as Puzzle 1828b. Players may load their saved solutions into the reposted puzzle.

Design an anti-inflammatory protein for COVID-19! This is a followup to Puzzle 1824, now with a helix fragment from a protein that is known to bind to the IL6R target. Players should focus on building up a protein with a large core of orange hydrophobics, and the best designs will also make additional contacts with the target. See our previous blog post for tips about designing a successful binder! Solutions from Puzzle 1824 are incompatible with this puzzle, so players may NOT load in previous work.

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.

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bkoep's picture
User offline. Last seen 14 hours 14 min ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff

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.

Joined: 04/23/2020
Groups: None


Joined: 09/24/2012
Groups: Go Science
Unideal locked loops?

Locked 116 is abego green which shows no candidate ideal loop in brueprint.
Locked 127-1238 are abego red but the ideal SS function keep them as a(non ideal) loop, which makes it difficult to build an ideal loop there.
7 invalid residues in the locked protein.

spvincent's picture
User offline. Last seen 9 hours 23 min ago. Offline
Joined: 12/07/2007
Groups: Contenders
There's a problem with the

There's a problem with the Ideal Loop filter here: no matter what I do I can't get ideal loops at the ends of the frozen helix and so end up with two non-ideal loops: it appears that others are having the same issue.

Susume's picture
User offline. Last seen 1 day 23 hours ago. Offline
Joined: 10/02/2011
Not possible to get ideal loops there

At the beginning of the locked helix, there is one locked residue in the green abego area. We don't have any ideal loops that have a green right before a helix, so no one will be able to get an ideal loop there. At the other end, there are two loop segments that are abego-red, but the helix backbone bonds are disrupted there, so they can't be counted as part of the good helix. We also don't have any ideal loops after a helix that start with two reds, so no one will be able to get an ideal loop there.
The "good" new is it's an even playing field - no one will be able to get the bonus for those two loops. The bad news is it's very frustrating and lots of players will spend lots of time trying in vain to fix it.

Susume's picture
User offline. Last seen 1 day 23 hours ago. Offline
Joined: 10/02/2011
Peptide bond 128-129 is bad

I turned on stick view and all the show options needed to see the O, N, and bondable hydrogen atoms. The peptide bond between 128 and 129 is bad - almost but not quite cis. The H on 129's N is on the same side of the backbone as the O at the end of 128. That makes it impossible to extend the helix - it makes a horrible U-turn there if tou try it. It is possible with aggressive banding and cutpoints to get it closer to trans, but not all the way to 180*. My guess is everybody's protein is going to be unrealistic at that spot.

bkoep's picture
User offline. Last seen 14 hours 14 min ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Good catch!

We've closed this puzzle and reposted it as Puzzle 1828b. In the reposted puzzle, the problem residues at both ends of the helix have been unlocked.

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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, Boehringer Ingelheim, RosettaCommons