Design an anti-inflammatory protein for COVID-19! Many COVID-19 complications are caused indirectly by the virus, and result from a severe over-stimulation of the human immune system. This kind of immune over-stimulation is commonly called a "cytokine storm." During a viral infection, immune cells normally release signaling proteins called cytokines, which inform the rest of the immune system about the infection and trigger inflammation. The inflammation is supposed to help the immune system fight off the infection, but too much inflammation can result in sepsis and organ failure.
One proposed strategy for treating serious COVID-19 cases is to prevent the "cytokine storm" by blocking certain cytokine signals. We want to design a protein that could block cytokine IL6, by binding to the IL6 receptor (IL6R).
In this puzzle, players are presented with the binding site of IL6R, which receives cytokine signals and triggers inflammation. The backbone and most of the sidechains are completely frozen, except for sidechains at the cytokine binding site. Players can design a new protein that binds to these sidechains, blocking interactions with the cytokine. In order to bind the IL6R target, designs will need to make lots of contacts and H-bonds with the spike protein at this 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 +275)
Penalizes extra residues inserted beyond the starting 152, at a cost of 55 points per residue. Players may use up to 157 residues in total.
Core Existence (max +1000)
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. Penalizes GLY, ALA, SER, THR in helices.
Yes, the target protein is a bit peculiar this way—a residue near the binding site makes a disulfide with a lone cysteine.
Note that the lone cysteine still has backbone polar atoms that may need to make hydrogen bonds if buried away from the surrounding water! (Try the Sticks view option and CPK coloring to see these more clearly.)
Sorry, I am rather a rookie here and I don't understand one thing with this puzzle:
Does the fixed part of the puzzle consist of several peptide fragments? There seem to be gaps in the backbone.
Yes, good observation! We're using a truncated model of the target, to help with software performance.
The target protein IL6R is much larger than what is shown in this puzzle (>200 residues). We could include those other residues in Foldit, but then we would have to score and render another 150 residues, which can cause lagging tools and choppy graphics. Since those extra residues don't participate in binding, we can omit them from the puzzle without affecting the scientific validity of the challenge.
To see a more complete model of the target (and how it binds the IL6 cytokine), see the PDB entry1P9M.
Showing the contradictions to this objective highlights areas on the IL6R. Showing the non-ideal loops (even though all were created originally with blueprint tool) shows both ends of the designed protein. The loop to nowhere.
Since you mention the backbone polar atoms, should we assume that the cysteine is actually connected to something, so we should try to put part of our protein too near that point in space?
