puzzle picture
1837: Coronavirus Binder Design: Round 9
Status: Closed

Summary

Name: 1837: Coronavirus Binder Design: Round 9
Status: Closed
Created: 05/13/2020
Points: 100
Expired: 05/20/2020 - 23:00
Difficulty: Intermediate
Description: Design a binder against coronavirus! This puzzle introduces a new objective: the Buried Unsats Objective detects "unsatisfied" polar atoms that cannot make hydrogen bonds with the water surrounding the protein. 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 will be unable to fix.) See the blog for more details about buried unsats, and for helpful tips to make a successful protein binder! Players will be unable to 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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1Go Science15,382100
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Comments

bkoep's picture
User offline. Last seen 11 hours 22 min ago. Offline
Joined: 11/15/2012
Groups: None
Objectives

Buried Unsats (max +500)
Detects polar atoms that cannot make 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 in helices.

Joined: 11/26/2012
Groups: None
Cysteine bridges?

Are cysteine bridges an option for this puzzle?

bkoep's picture
User offline. Last seen 11 hours 22 min ago. Offline
Joined: 11/15/2012
Groups: None
Possible

You can design disulfide bonds into your protein, and they might help stabilize your protein. But we do not think disulfides are necessary, and Foldit will not reward these with a score bonus.

spvincent's picture
User offline. Last seen 5 hours 20 min ago. Offline
Joined: 12/07/2007
Groups: Contenders
Where are the sugars?

The coronavirus spike protein is supposed to be a glycoprotein. So why aren't we seeing any sugars in the locked region?

Joined: 06/24/2008
Groups: Void Crushers
sugars

Foldit gods used the sugars in their morning coffee.

Joined: 08/11/2010
Do tell! :-)

Do tell! :-)

bkoep's picture
User offline. Last seen 11 hours 22 min ago. Offline
Joined: 11/15/2012
Groups: None
Great question!

Fortunately there are no sugars on this part of the spike protein. These puzzles use only the receptor-binding domain (RBD) of the spike protein—the part the interacts with the human receptor.

The rest of the spike protein is much larger, and much of it is covered with such sugars. Because the sugars are polar and "floppier" than protein side chains, it would be much harder to design a protein that sticks to a glycosylated region of the spike protein. In that sense, we are lucky that the RBD region is not glycosylated.

grogar7's picture
User offline. Last seen 1 hour 15 min ago. Offline
Joined: 10/03/2011
500 maximum for buried polars filter?

The puzzle comments indicate 500 points maximum for buried polars filter, but I have 550 points (7 buried polars). I cannot seem to load an image here. Will share with scientists.

bkoep's picture
User offline. Last seen 11 hours 22 min ago. Offline
Joined: 11/15/2012
Groups: None
Target BUNS

That's great! You must have found a way to satisfy one of the BUNS atoms on the target.

grogar7's picture
User offline. Last seen 1 hour 15 min ago. Offline
Joined: 10/03/2011
problem with Buried Polars filter

I have noticed that moving the designed protein well away from the target (so there is no interaction with the target) and simply rotating it with the move tool will change the number of buried polars. Explanation?

bkoep's picture
User offline. Last seen 11 hours 22 min ago. Offline
Joined: 11/15/2012
Groups: None
Surface area approximations

This is not surprising, and has to do with some technical details of the BUNS calculation.

To detect whether a polar atom can make H-bonds with surrounding water, we need to calculate how much of that atom's "surface" is exposed. To calculate this exactly is slow to do; to speed things up, we use an approximation that involves slicing the protein into a 3D grid of voxels. This method is much faster, but is also a little unstable, because simple rotations and translations affect how the protein aligns to that 3D grid.

We are exploring ways to avoid this approximation, but these will probably make the BUNS objective slower to compute.

spdenne's picture
User offline. Last seen 39 min 24 sec ago. Offline
Joined: 10/01/2011
Groups: Void Crushers
I just saved my 1843 solution

I just saved my 1843 solution from the main client with 10 BUNS, and loading it in the devprev client resulted in 13 BUNS, and a lower score.

grogar7's picture
User offline. Last seen 1 hour 15 min ago. Offline
Joined: 10/03/2011
Thanks, bkoep

Thanks, bkoep, for your replies to my concerns above. Especially interesting are the Surface Area approximations and the implications for score when this filter is active.

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