puzzle picture
1811: Coronavirus Binder Design: Round 3
Status: Closed

Summary

Name: 1811: Coronavirus Binder Design: Round 3
Status: Closed
Created: 03/11/2020
Points: 100
Expired: 03/19/2020 - 23:00
Difficulty: Intermediate
Description: Design a binder against coronavirus! This is Foldit's third coronavirus puzzle, which challenges players to design an antiviral protein that could bind to the 2019 virus and disrupt viral infection. This puzzle provides a helix fragment that is already known to bind to the coronavirus, and Foldit players can design a new protein that includes this fragment. 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 latest video update or the Foldit blog for tips about designing a successful binder! Solutions from previous puzzles are incompatible with this puzzle, so players may NOT load in previous work.

In late 2019, a new highly-infections virus emerged out of Wuhan, China. This virus belongs to the coronavirus family, and is similar to the virus that caused the SARS epidemic in 2002. Coronaviruses display a "spike" protein on their surface, which binds tightly to a receptor protein found on the surface of human cells. Once the coronavirus spike binds to the human receptor, the virus can infect the human cell and replicate. In recent weeks, researchers have determined the structure of the 2019 coronavirus spike protein and how it binds to human receptors. If we can design a protein that binds to this coronavirus spike protein, it could be used to block the interaction with human cells and halt infection!

In this puzzle, players are presented with the binding site of the coronavirus spike protein. The backbone and most of the sidechains are completely frozen, except for flexible sidechains at the binding site, where the spike protein normally interacts with the human receptor protein. This puzzle also includes helix fragment from the human receptor. 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 human receptor. Final designs will need to make additional hydrophobic contacts and H-bonds with the flexible sidechains at the target 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

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Comments

bkoep's picture
User offline. Last seen 3 hours 36 min ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Objectives

Residue Count (max +550)
Penalizes extra residues inserted beyond the starting 196, at a cost of 55 points per residue. Players may use up to 206 residues in total.

Core Existence (max +2400)
Ensures that at least 28 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: 06/24/2008
Groups: Void Crushers
Ideal Loops

On 1811 I am mistaken or are there two non-Ideal Loops we can not change? One at seg 146 the other at seg 159.

LociOiling's picture
User offline. Last seen 24 min 16 sec ago. Offline
Joined: 12/27/2012
Groups: Beta Folders
those permanent cutpoints are a challenge...

This puzzle starts out in an unusual position, with two long straight blue-gray lines at either end of a gray helix. The gray color indicates the helix is locked.

There's also a separate gray part with a more complex shape, that's the coronavirus spike protein, as seen in the previous puzzles.

The locked helix is the "helix fragment from the human receptor", and it's in a spot where it's already bound to the coronavirus spike.

The blue-gray lines are permanent cutpoints, meaning you can't close them, no matter how close together the ends are. You're likely to get non-ideal loops around these permanent cuts. The remix tool doesn't work if there's a cut, so making an ideal loop may be a challenge.

At the other end of the permanent cuts, there are two sections of designable extended chain. Just like in the previous puzzle, which had one long extended chain, you're free to shape these extended chains however you'd like. You'll also need to move the ends closer to the locked helix.

The locked helix has some colorful sidechains. Unlike the colorful sidechains on the coronavirus part, the colorful sidechains on the locked helix can mutate. They start out as valine, but can change to other amino acids.

The side of the locked helix closest to the coronavirus has gray sidechains, meaning that they are locked and can't mutate.

Susume's picture
User offline. Last seen 5 hours 56 min ago. Offline
Joined: 10/02/2011
One way to "fix" the permanent cutpoints

Those permanent cutpoints are a pain. I started out by making both flexible sections into helices, moving them close to the frozen helix, then rubberbanding in the way that helix-straightening scripts do: each residue r to r+3 and to r+4. I just did this for the several residues around the cuts, so the flexible helices were banded to the frozen helix.

I then froze the flexible helices and wiggled, letting the bands and the score pull the flexible parts into a good helix position relative to the frozen helix. Then at least I knew the cutpoints had valid lengths and angles.

From there I avoided moving the one flexible segment closest to each end of the frozen helix. You can use the pin tool (in view menu) to pin each of those two segments in space so that tools such as blueprint only move the other end of the flexible helix.

frood66's picture
User offline. Last seen 6 days 12 hours ago. Offline
Joined: 09/20/2011
Groups: Marvin's bunch
we need the ability

we need the ability to use Blue prints that involve the ends of the frozen segment - until we have that any solutions will be by luck - the inability to do this simply means that we waste a stupid amount of time - and create fewer workable solutions.

spvincent's picture
User offline. Last seen 3 hours 45 min ago. Offline
Joined: 12/07/2007
Groups: Contenders
I agree: this type of

I agree: this type of cutpoint currently is a real pain.

jeff101's picture
User offline. Last seen 30 min 28 sec ago. Offline
Joined: 04/20/2012
Groups: Go Science
Please summarize this puzzle in terms of its initial residue #'s

I haven't started this puzzle yet, but it would
help me a lot if someone would summarize the goals
of this puzzle in terms of residue #'s in this
puzzle's starting structure. For example, which
residues can we mutate? Which can we delete?
Which have mobile backbones? Which have mobile
sidechains? Which residues are we trying to bind
to or block with the mobile and mutable parts
of the protein?

Thanks!

Susume's picture
User offline. Last seen 5 hours 56 min ago. Offline
Joined: 10/02/2011
Use blueprint to see...

I just noticed last night that in the blueprint tool, above the row of letters, there is a checkbox for ABEGO colors. If you uncheck it, the letters in the blueprint tool will be colored the same as your protein, and you can see which ones are gray (locked) and which are bright (unlocked).

jeff101's picture
User offline. Last seen 30 min 28 sec ago. Offline
Joined: 04/20/2012
Groups: Go Science
Loci's Coronavirus Videos:

Below has links to at least 3 videos by LociOiling about
the Foldit Coronavirus Puzzles so far. Thanks for making
and sharing them, Loci!

https://fold.it/portal/node/2009051

jeacom's picture
User offline. Last seen 26 weeks 19 hours ago. Offline
Joined: 06/02/2016
Groups: Go Science
cuts are pain really.

I agree with everyone here, those cuts are absolute pain.

LociOiling's picture
User offline. Last seen 24 min 16 sec ago. Offline
Joined: 12/27/2012
Groups: Beta Folders
paint by numbers

As requested by jeff101, here's the breakdown on the segment numbers at the start of puzzle 1811. This information is available in print protein 2.8. (A long-stalled update to print protein is in the works, Real Soon Now.)

It's possible to insert and delete segments in the binder part, which could change some of the numbers.

Foldit doesn't identify chains, but in the PDB or a similar source, segment 1-117 would be chain A, and 118-197 would be chain B.

Chain A is part of the CoV spike protein, and chain B is the binder that we're designing. Part of the binder is already designed for us, and locked in place.

The locked backbone segments are:

  • chain A, CoV spike: 1-117
  • chain B, binder: 147-170

Even is when a segment's backbone is locked, the sidechain may be unlocked.

For the CoV spike in chain A, the unlocked sidechains representing the binding site are:

  • 1-1
  • 7-10
  • 12-13
  • 15-15
  • 17-17
  • 20-21
  • 23-25
  • 35-35
  • 39-39
  • 48-53
  • 57-57
  • 59-60
  • 76-77
  • 79-80
  • 85-91
  • 93-109

For the binder in chain B, the unlocked sidechains represent segments that can be designed:

  • 118-147
  • 149-150
  • 152-153
  • 156-157
  • 160-161
  • 163-164
  • 167-197

Somewhat unusually, the chain B binder has segments that are locked, but can be mutated:

  • 147-147
  • 149-150
  • 152-153
  • 156-157
  • 160-161
  • 163-164
  • 167-170
jeff101's picture
User offline. Last seen 30 min 28 sec ago. Offline
Joined: 04/20/2012
Groups: Go Science
Thanks Loci!

Your post above is very helpful.

Susume's picture
User offline. Last seen 5 hours 56 min ago. Offline
Joined: 10/02/2011
another video

Here's the video (edited for length and clarity, thanks ianh!) of my stream from March 14, talking about corona virus strategy and also one method of approaching the permanent cutpoints.

https://www.youtube.com/watch?v=CzSCkJ0w4Dk&t=2s

LociOiling's picture
User offline. Last seen 24 min 16 sec ago. Offline
Joined: 12/27/2012
Groups: Beta Folders
"mystery" points in frozen, locked segments

We're getting closer to an updated "print protein" recipe, and I noticed an interesting discrepancy.

In 1811, if you hover over segment 1 and hit "tab", it shows the segment score as "-0.0". While it's not clear how -0 differs from 0, that's fine.

If you enter this one-line recipe and run it:

print ( current.GetSegmentEnergyScore ( 1 ) )

the result is non-zero:

-16.759085881012

Segment 2 is similar, showing a zero score in the segment information window, but reporting a score of 50.183449869801 using the recipe.

Just for the sake of completeness, if you run current.GetSegmentEnergySubscore for all subscores, you get zero. This little recipe demonstrates:

SEG = 2

tscore = current.GetSegmentEnergyScore ( SEG ) 
    
print ( "total score for segment " .. SEG .. " = " .. tscore )

local Subs = puzzle.GetPuzzleSubscoreNames ()

local tsubs = 0
for ii = 1, #Subs do
    local subscore = current.GetSegmentEnergySubscore ( SEG, Subs [ ii ] )
    print ( "score part " .. Subs [ ii ] .. ", score = " .. subscore )
    tsubs = tsubs + subscore
end
print ( "total of all subscores for segment " .. SEG .. " = " .. tsubs ) 

The nice part is that when you total up a bunch of -0 scores, you get plain old 0.

It's not clear to me why the segments with all zero subscores still report a score. It may have something to do with keeping the different versions of the score consistent, or it may just be a glitch. We've probably been seeing similar results on other, similar puzzles like the aflatoxin series, but I haven't gone back to check.

Anyway, this is for jeff101 and anyone else who likes to explore the boundaries. The new print protein will have a couple of new columns to highlight issues of this type. Worst case, you'll have all the numbers, and can add them up as you see fit.

frood66's picture
User offline. Last seen 6 days 12 hours ago. Offline
Joined: 09/20/2011
Groups: Marvin's bunch
here's something

We are asked to use Blue prints for the loops - ok

yet I have a loop that is 4 sets long - and passes the filter........there is no Helix to helix BPrint that is 4 sets long.

This is not new info for many I think - but it begs a question....

Dan we please have this BPrint situation sorted properly?

Just asking - thx

bkoep's picture
User offline. Last seen 3 hours 36 min ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Please share with scientists!

If you can share your solution (and maybe put "Blueprint bug" in the title), that will help us track down the issue!

Joined: 03/18/2020
Groups: blue
update

please

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