bertro Lv 1
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1000: Breach Ebola's Defences!
Closed since over 11 years ago
Intermediate Overall DesignSummary
- Created
- October 18, 2014
- Expires
- Max points
- 100
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.
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Comments
inkycatz Lv 1
http://fold.it/portal/foldit1000 This puzzle will appear when the client update goes out.
Susume Lv 1
If you turn on voids in the view menu (as recommended), it's important to turn them off before you minimize the game if you have a script running. If you leave them on, there may be a long delay when you restore the game window during which the game appears frozen. Depending how long the script has been running in the minimized game window, this delay can be many minutes long. If you forget to turn voids off and the game becomes frozen, don't kill the game; it will most likely recover if you let it sit for several minutes.
bkoep Staff Lv 1
This issue should be fixed with the client update accompanying this puzzle. A minimized client will restore normally now, even with voids turned on.
alwen Lv 1
The image showing the cap was there when I first looked at this puzzle page, but is now showing as a broken-image icon.
And gives a 404 error when I try to look at the link itself.
beta_helix Staff Lv 1
it's back now!
jamiexq Lv 1
You have nine different starting configs but we can only share 5 with scientists.
v_mulligan Lv 1
It's unlikely that every one of these loop conformations will yield good places to place residues. Pick your favourite and try to focus on that. We gave you 9 because we don't know a priori which will be the good ones and which will be the poor ones.
jamiexq Lv 1
Should the red constraints be resolved (or protein piece so close they are not showing)?
v_mulligan Lv 1
No, not necessarily. The constraints are "flat-bottomed" – that is, there's a penalty for being far from the binding pocket, but once you get close to the binding pocket, the penalty function levels off so that being 1 Angstrom away is no better than being 2 Angstroms away. Just make sure that you're in the pocket and focus on making good contacts.