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.
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.
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.
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.
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?
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.
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
</ul>
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
</ul>
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
</ul>
Somewhat unusually, the chain B binder has segments that are locked, but can be mutated:
