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1880: Coronavirus Binder Design: Round 16

Closed since about 2 years ago

Intermediate Overall Design

Summary


Created
August 20, 2020
Expires
Max points
100
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.

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Comments


bkoep Staff Lv 1

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.

BootsMcGraw Lv 1

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.

Formula350 Lv 1

For anyone else unable to get the puzzle to load, this <brequires the update that was released today before the puzzle was launched.

OWM3 Lv 1

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".

bkoep Staff Lv 1

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.

Bletchley Park Lv 1

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 ?

spmm Lv 1

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

jeff101 Lv 1

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.