Note: This puzzle replaces Puzzle 1828, which had some errors in the protein backbone. Players may load solutions saved in Puzzle 1828.
Design an anti-inflammatory protein for COVID-19! This is a followup to Puzzle 1824, now with a helix fragment from a protein that is known to bind to the IL6R target. Players should focus on building up a protein with a large core of orange hydrophobics, and the best designs will also make additional contacts with the target. See our previous blog post for tips about designing a successful binder! Solutions from Puzzle 1824 are incompatible with this puzzle, so players may NOT load in previous work.
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.
Residue Count (max +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.
I think recipes would work better on puzzles like
this if the Ideal Loops Bonus depended on the total #
of residues in non-ideal loops rather than the # of
non-ideal loops. This way, shorter non-ideal loops would
score better than longer ones, and if you changed a
14-residue non-ideal loop into 2 non-ideal loops each
with length 5, your score would improve.
Is there value in a anti-inflammatory protein also capable of bonding to the covid spike? Obviously bonding to IL6R would take priority, but every protein has multiple angles and there may be a non intrusive way to allow one side to bond to part of the spike.
That's an interesting idea! But, in general, we prefer to have drugs that interact each with a single target. This gives doctors greater control over the treatment program. I think this would outweigh any advantages to having two functions on the same molecule (in this case, at least).
Ideally, we'd like to have one drug that targets the CoV spike, and one that targets IL6R. If a doctor decides both drugs are necessary, then they can both be administered (and hopefully there are no complex drug interactions). If the same drug targets both IL6R and CoV spike, then there is no way for a doctor to treat one without affecting the other.
