First look at coronavirus solutions

Today was the final day for Puzzle 1805b: Coronavirus Spike Protein Binder Design! If you didn't get a chance to participate, or if you have more ideas to try, don't worry. There is a new and improved Round 2 puzzle where you can continue to work on your designs!

Now that our first puzzle has closed, scientists at the Institute for Protein Design at the University of Washington School of Medicine will take a close look at Foldit players' solutions. At first this will involve an intensive computational analysis of Foldit players' designs. We will try to assess both whether the designed proteins will fold correctly and if they might bind to the coronavirus target.

Promising solutions will then advance to laboratory testing, where we will manufacture select Foldit player-designed proteins and test to see if they stick to coronavirus spike protein. (Don't worry, scientists can safely experiment with the coronavirus spike protein without exposing ourselves to live virus)

In the mean time, we've already had a chance to look at some initial solutions from Foldit players. Below, we take a brief look at some of our favorite solutions so far, what we like about them, and what can be improved.

Hydrophobic packing

In Foldit, orange sidechains are hydrophobic. This means that they like to be buried, away from the water that surrounds the outside of the protein. Proteins naturally tend to fold up in ways that bury these orange hydrophobics in the protein core. This is called the hydrophobic effect.

This same hydrophobic effect can also drive protein molecules to stick together! If two proteins each have small, complementary patches of orange hydrophobic sidechains on their surface (exposed to surrounding water), then the two proteins will tend to stick together in order to hide these sidechains.

For a designed protein to fold, we need to make sure it has a significant core with lots of buried orange sidechains. And for it to bind against the coronavirus target, it will also need to bury orange sidechains at the binding interface. However, if the designed protein has too many orange sidechains on its surface, it will misfold.

Below is an excellent designed protein! It has a significant core of buried orange hydrophobics, and the surface mostly consists of blue sidechains. In addition, almost all of the residues in the design form alpha-helices; this is a very stable configuration for the protein backbone. So, if we were to synthesize this protein in the lab, there's a good chance it would fold up into this desired shape!

At the binding interface (on the right), we can see that this design makes close contacts with two bulky hydrophobic sidechains (highlighted in purple) on the coronavirus target. This will likely help to bury the bulky hydrophobics away from the surrounding water, and may result in tight binding between the designed protein and coronavirus target!

Hydrogen bonds

The coronavirus spike protein is an especially difficult target to bind because there are not very many orange hydrophobics on its surface. In Foldit, blue sidechains are hydrophilic. These sidechains have polar oxygen and nitrogen atoms that can make very stable hydrogen bonds with the water surrounding the protein. For this reason, blue sidechains normally like to be exposed on the surface of the protein.

If we want to bind to the coronavirus target, our designed protein will probably have to bury some of these blue sidechains away from water. In other words, our designed binder will disrupt the stable hydrogen bonds that the blue sidechains normally make with water. The only way to compensate for this is by making hydrogen bonds to all of the oxygens and nitrogens that are buried at the interface.

In Foldit, you can see polar oxygen and nitrogen atoms by setting your View Settings to Hydro/Score+CPK coloring. This will color all oxygen and nitrogen atoms red and blue. Polar oxygen and nitrogens on the coronavirus target will need to be matched with polar atoms on the design to make hydrogen bonds!

Below is another excellent design from Foldit players! Again, this design has lots of orange sidechains buried in the core of the protein, with blue sidechains on the surface. This design also has lots of structure: the protein forms beta-sheets in addition to alpha-helices, which is another stable arrangement. So we think this design is likely to fold up correctly if tested in the lab!

If we look at the binding interface for this design (on the right), we see some very nice hydrogen bonding with some polar oxygens on the coronavirus target! Since these oxygens can normally make hydrogen bonds with surrounding water, it's very important that our designed binder can make these replacement hydrogen bonds.

However, if we look closer, we can see that our design introduces new polar atoms that are buried at the binding site, and not all of them make hydrogen bonds! The hydrogens numbered 1 through 4 are not making hydrogen bonds, and this could interfere with binding. This designed binder will tend to float away from the coronavirus target, so that all of these polar atoms can make hydrogen bonds with the surrounding water.

Binding site

This last binder design also looks very promising at first glance. We see that the designed protein itself has lots of orange sidechains buried in the core, with blue sidechains on the surface, so it is likely to fold up correctly. We also see that there are lots of orange sidechains that are buried at the interface with the coronavirus target, so this should result in really tight binding between the design and the target!

However, this design binds to the wrong side of the coronavirus target! We see that this protein is designed next to the frozen section of the coronavirus protein, away from the flexible sidechains at the target binding site. If we overlay this design with the normal human receptor (highlighted in purple), we see that there is no overlap between the design and the human receptor!

This means that the coronavirus protein is capable of binding to both the design and the human receptor at the same time. So even if this design binds to coronavirus protein, it will probably not block the infection pathway of the virus.

In the new Round 2 puzzle, we amended the coronavirus target so that these off-target residues do not contribute to your Foldit score. In order to get the best score (and design an effective antiviral protein) players should focus on the flexible blue and orange sidechains at the normal binding interface.

Good luck, and happy folding!

( Posted by  bkoep 172 3336  |  Thu, 03/05/2020 - 23:16  |  4 comments )
6
jawz101's picture
User offline. Last seen 19 hours 51 min ago. Offline
Joined: 03/07/2020
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:(

It feels like the game should explain this in 5 year old language. I'm reading a lot of jargon in here but most of us are visual. Can't you just circle something and say "try to get your pieces over here somewhere. Putting it here won't work. We need these orange thingies pointing in and these blue thingies pointing out."

Joined: 05/09/2008
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we wish it were that simple!

Unfortunately jawz101, it's a lot more complicated and simplifying everything too much can result in wasted time on the part of you and other players (which we'd like to avoid).

We hope that our latest blogpost, while a long read, will explain many of these important concepts with nice visual examples:

https://fold.it/portal/node/2009115

mwm64's picture
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Joined: 05/21/2020
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Binding site highlighting *would* be nice...

If there were some way to "flash" the binding sites we want to cover so they really stand out, it would make getting started on theses a lot easier...

LociOiling's picture
User offline. Last seen 3 hours 43 min ago. Offline
Joined: 12/27/2012
Groups: Beta Folders
view options can help

There are a couple of ways to show the segments/sidechains in the coronavirus target that are part of the binding site.

Make sure you have "show advanced GUI" checked under General Options, control + t.

In View Options select something like EnzDes or CPK coloring and one of the Cartoon views.

Under View Sidechains, select "Show All (Slow)".

Now the unlocked sidechains around the binding site appear in color, while the locked sidechains appear in the same gray as the backbone as the mostly locked coronavirus target.

The hotkey control + shift + x gets you EnzDes and Cartoon Thin. Then shift + a displays all sidechains, and shift + d hides them again.

In the selection interface, another way to see the binding site is to select all, control + a. The segments with unlocked sidechains in the target show up in the blue selection color. This is actually not a bad way to see the binding site, but it's easy to lose the selection, such as when trying to use the move tool.

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