Description:

For our one thousandth puzzle, we've got a particularly challenging task for you. We have posted a few past puzzles in which we have asked players to design peptides and small proteins that are able to bind to a binding site on the Ebola binding protein. The glycoprotein uses this site to latch onto a human cell membrane protein as a first step in invading host cells, which means that something binding at this site should hinder viral entry into cells.



Unfortunately, there is a complication: the virus has a defence. The Ebola glycoprotein, when it is first made, has a "cap" that covers the binding site. This cap is cleaved off just before the virus attaches itself to the human protein that it uses to invade host cells, but it does represent an obstacle if we want a binder to block this site at an earlier stage. We need our binders to bind despite the cap. Fortunately, the loop on the cap that actually blocks the binding site is probably fairly flexible, which means that it could potentially bend out of the way if an artificial binder has enough affinity for the binding site. See the puzzle description on the Foldit website (http://fold.it/portal/node/1998572/) for an image showing the cap, cap loop, and binding pocket.







For this puzzle, we're giving you nine starting states, each of which has the loop in the cap that normally covers the binding pocket in a different conformation that exposes the pocket. We want you to dock a five-amino acid peptide into the pocket, and to design the sequence of the middle three amino acid residues. You can switch between the starting conformations by resetting the puzzle.



Some considerations:

--Use the void view, and try to minimize the number of voids in the pocket by using hydrophobic residues that maximally fill the space.

--Interactions with the cap may not be as desirable as interactions with the pocket, since we want our binder to bind whether or not the cap is present.

--The usual considerations (good shape- and charge-complementarity between the binder and the pocket, etc.) all apply. Your score should be used as a guide, but it's always possible that the best solution won't have the top score, so use the "share with scientists" button!

--The most plausible player designs (whether these are top-scoring or shared with scientists) will be used as a starting point for the design of full-length binders.



Enjoy puzzle 1000!



Update: A few users have pointed out an unintended exploit that allows them to get additional points: if you delete the first and last residues of the peptide, and then add them back, they are now designable residues, permitting you to design five positions instead of the intended 3 (and thereby get more points). This doesn't invalidate the scientific results, but we don't want some people to have an unfair advantage, so we want everyone to know that this exploit exists in this puzzle.