Design a binder against coronavirus! We're challenging players to design an antiviral protein that could bind to the 2019 coronavirus spike protein and disrupt viral infection. The starting structure is a solution designed by Steven Pletsch in our previous Round 3 puzzle. This solution makes an excellent interface with the target, but we're concerned that the binder may not fold properly, especially the loops connecting the three helices. We're asking Foldit players to try and improve this design so that it folds up correctly and can bind to the target! Players also have freedom to redesign an entirely new solution from scratch.
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 normally interacts with the human receptor. Players can design a new protein that binds to these sidechains, blocking interactions with the human receptor. Successful binder 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.
Residue Count (max +440)
Penalizes extra residues inserted beyond the starting 196, at a cost of 55 points per residue. Players may use up to 204 residues in total.
Interaction Energy (max +500)
Monitors that all PHE, TYR, and TRP residues are scoring well.
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 in helices.
What strikes me is that a simple mutate and wiggle round (with frozen interconnects) will up the score so much that I wonder if this is an early stage version of Steven Pletsch's solution or an intentionally downgraded version. Is there a story behind this ?
this was one i made quickly and abandoned in favor of another design, i simply didn't like a big 3 helix design because i thought it would be difficult to get a max core bonus
Thank you Steven. Still the mystery remains, when I keep the sidechains that make up the connections the score is lower than when I let these sidechains run free while mutating.
@bkoep; Should we keep the sidechains which are given, focus on the backbone to improve the score or let the sidechains mutate as well in order to optimize the score, possibly losing the current links (and optionally creating other links) with the spike protein ?
• The protein we are designing will fold as intended.
• That it will bind to the virus active sight as intended.
• That the virus, sensing it’s a cell wall, will destroy it.
This design already has a nice-looking interface, so it may be sufficient to fix the loops and retain the given sidechains at the interface.
That said, there is always room for improvement! If we were certain about the given sidechains, we would have frozen them. Even though our binder metrics are not available to players yet (we're working on it!), optimizing your score is still a good strategy for finding an effective binder.
