Design an anti-inflammatory protein for COVID-19! This puzzle uses the new Buried Unsats Objective 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 target. (Note that this target protein includes 15 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 will be unable to load solutions from previous puzzles.
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). For more details, see our recent video update about blocking the cytokine storm.
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. This puzzle also includes a binding helix fragment from the IL6 cytokine. 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 IL6 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.
Sorry I didn't see this comment before the puzzle closed!
The problem we are trying to avoid is excessive alanine. Foldit players discovered that you can pack helices really tightly using exclusively ALA. The tight packing gives really high Foldit scores, but we don't expect these designs to fold as well as designs with better "interdigitation" between sidechains in the core.
Ideally, we would put a soft limit on the amount of ALA allowed in designs (it's on our to-do list). In the meantime, we found that we can get by without ALA in secondary structure, and it seems that Foldit players can design super-stable proteins without any ALA at all.
Dear scientists, just now I used "upload to scientists" to share another huge bonding improvement to my previously uploaded suggested solutions. Now, there is a total of 2/3 hydrophobic interactions (depending on which of my solutions you look at), 3 hydrogen bonds and 2 satisfied BUNS all within the target, which I think make it a very strong and possible binder.
Otherwise, as I am fairly new to this subject, I would highly appreciate it if you could have a look at it and give me feedback (Am I even on the right track?), either here or via mail or whatever possibilities there are.
Is there a place to share and discuss such topics with other players?
Feel free to join the Foldit discord to share and discuss topics with other players and developers. https://discord.com/invite/Ffgx2KJ
Please let me know if you have any additional questions.
