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 Susume 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 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.
You state that the loops connecting the helices need redesigning and yet they satisfy the Ideal Loops filter. What other criteria are we supposed to use?
Great question! The problem with these loops is very subtle, and it will probably be important to pay attention to the "Backbone" subscore for these residues (to see residue subscores, mouse-over a residue and press the TAB key).
The test that flagged these loops is much more sensitive (it looks at finer per-atom RMSD) than the Ideal Loop Objective (which looks at coarser ABEGO bins). So, although the backbone torsions fall within the correct ABEGO bins, they may still be outside the most common distribution of torsion values.
Since I´ve seen a lot of players improve in comparison to early rounds of this puzzle I am curious if there will be any additional selections for lab testing? Or is there an updated video discussion on some designs planned? I´d like to see that again.
