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1880: Coronavirus Binder Design: Round 16
Status: Closed

Summary

Name: 1880: Coronavirus Binder Design: Round 16
Status: Closed
Created: 08/20/2020
Points: 100
Expired: 08/27/2020 - 23:00
Difficulty: Intermediate
Description: Design a binder against coronavirus! This puzzle introduces new binder metrics to measure the DDG, SASA, and Shape Complementarity of your design. Because the metrics are slow and must be run manually, they are available as optional Objectives and will not award any bonuses or penalties. To calculate these metrics, open the Objectives dropdown panel and click "Run All." Other Objectives are still in effect. This puzzle prohibits SER and THR in helices, which may make it harder to satisfy BUNS, but should help the helices to fold correctly. Remember, if your designed protein creates Buried Unsats, then it will be less likely to fold and bind to the coronavirus target. (Note that this target protein includes 8 buried unsats that players may be unable to fix.) See the blog for more details about buried unsats, and for helpful tips to make a successful protein binder! Players may not load solutions from previous puzzles.

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. Players can design a new protein that binds to these sidechains, blocking interactions with the human receptor. In order to bind the coronavirus target, designs will need to make lots of hydrophobic contacts and H-bonds with the flexible sidechains at the 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 1 day 5 hours ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Objectives

Binder DDG
The binding energy of your design to the target. The target DDG is -40.0 or less.

Binder SASA
The solvent-accessible surface area that is lost upon binding. The target SASA is 1500 or more.

Binder Shape Complementarity
Measures how well your binder fits the contours of the target surface. The target Shape Complementarity is 0.60 or more.

Buried Unsats (max +20)
Penalizes 60 points for each polar atom that cannot make any hydrogen bonds. Note that the frozen target includes 8 buried unsats that may be impossible for players to satisfy.

Residue Count (max +275)
Penalizes extra residues inserted beyond the 177, at a cost of 55 points per residue. Players may use up to 182 residues in total.

Core Existence (max +2400)
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.

spmm's picture
User offline. Last seen 1 week 5 days ago. Offline
Joined: 08/05/2010
Groups: Void Crushers
DDG - negative binding score

target is -40.0 or less - may be a bit counterintuitive for some sleepy folders :)

jeff101's picture
User offline. Last seen 4 hours 1 min ago. Offline
Joined: 04/20/2012
Groups: Go Science
DDG

If the target DDG is -40.0 or less,
is a DDG of -60.0 better than -40.0, or
is a DDG of -20.0 better than -40.0 ?

https://fold.it/portal/node/2009115
says "A more negative DDG (or ΔΔG)
indicates stronger binding." Then it
gives an example where a Foldit design
with a DDG of -45.0 kcal/mol is
predicted to bind tighter than ACE2
with a DDG of -39.3 kcal/mol.

Joined: 12/06/2008
Groups: Contenders
I can't access this puzzle.

I can't access this puzzle. When I try to load it, I get the error message 'unused key bonus_coeff'.

Does this mean we are required to load the new update before we can play this puzzle? My two machines are currently in the middle of some long scripts I don't want to interrupt.

Joined: 09/29/2016
Groups: Gargleblasters
Yessir

For anyone else unable to get the puzzle to load, this

bkoep's picture
User offline. Last seen 1 day 5 hours ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Update required

Yes, the August 20 update is required to play Puzzle 1880.

Joined: 05/19/2009
Groups: Contenders
Baker lab already publishes working binders ?

I was surprised to accidentally find this publication on a series of apparently successful binder proteins coming from the Baker lab.

https://www.biorxiv.org/content/10.1101/2020.08.03.234914v1.full

Can you please elaborate on the findings ?

bkoep's picture
User offline. Last seen 1 day 5 hours ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
See Forum

Yes! Some Baker Lab scientists used computational methods to develop binders extremely quickly. These are very exciting results and we may dig into details in a later blog post.

There is also a forum discussion here.

Joined: 05/19/2009
Groups: Contenders
Would like to read more on the computational methods too !

Thank you for the quick answer and the link, I'm also very curious about the computational methods, can there please be a blog post on those too ? Is there a way we can improve / speedup our folding activities using computational methods as well ?

OWM3's picture
User offline. Last seen 4 hours 28 min ago. Offline
Joined: 03/08/2020
Groups: Gargleblasters
The Bug

Each time I press on "DDG Score" button - each time I get different values (from -18 to -20). If you want to debug this issue - I've shared a solution with 14363 points "for scientists".

Joined: 09/29/2016
Groups: Gargleblasters
Is it while you're Wiggling? -- UPDATED

Because if your protein is actively changing, even fractional points, running ANY of the New Metric filters is going to produce a different result.

For me, with no tool running, they all consistently reports the same score (even if ran individually).

To answer that for him, no he was not Wiggling. All he's doing is, with a "still" protein, pressing Run on DDG.

Since OWM and I are on the same team, I'm able to load his share.
I can confirm that for his pose, it does in fact churn out different results for DDG on almost ever Run.
My Tests: -18.8, -20.4, -18.8, -18.8, -19.2, *a few minutes later pressed again* -19.2, -18.9

SASA and SC do not vary. This also occurs when using Run All.

While I can't say I've personally ever ran the filters multiple times back to back on the same pose, I did try on my own design before loading OWM's, and mine did not exhibit this, only his Shared pose does.

Officially adding it to the internal Google Doc (my Community Crash Compendium) since it's reproducible on two systems, across different OS environments.

bkoep's picture
User offline. Last seen 1 day 5 hours ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Good catch!

Good catch! There is a random component to the algorithm in the DDG Objective. In the future, we can simply turn off this random component, but in the long term we should probably try to come up a better non-random alternative for this component.

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