Design a binder against coronavirus! In this puzzle, the Buried Unsats Objective will not award any bonus or penalty points, but you can still use it to detect "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 may be unable to fix.) See the blog for more details about buried unsats, and for helpful tips to make a successful protein binder! Players may not 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.
Buried Unsats (max +500 +0)
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. This Objective awards no bonus or penalty.
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 and helices.
Which is the available surface on the frozen part of the puzzle?
As far as I understood, mainly the nick (notch?) of the "saddle" of the frozen part in this puzzle is accessible for the designed protein.
Do the flanks of this "saddle" also belong to the accessible parts of the receptor-binding-domain or are they blocked by other structures?
(e.g. as the spike protein is a trimer, these parts may be covered by another chain of the trimer.)
Only the flexible orange/blue sidechains should be targeted. This includes some of the flanking regions of around the "saddle." These are the residues that the spike uses to recognize the human ACE2 receptor, and we want to block those residues with our designed binder.
Other parts of the target have frozen gray sidechains. These should be avoided because they are not involved in ACE2 recognition (so we don't need to target them), or because they would be blocked by other parts of the spike protein.
