1000: Breach Ebola's Defences!

Closed since over 11 years ago

Summary

• Created: October 18, 2014
• Expires: October 27, 2014 at 23:00 UTC
• Max points: 100

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.

Top groups

• 31. Deleted group pts. 10,740
• 32. Geekdo 1 pt. 10,550
• 33. Atlanta 1 pt. 10,423
• 34. Window Group 1 pt. 8,210

Top soloists

• 1. gloverd 100 pts. 11,193
• 2. jeff101 99 pts. 11,185
• 3. Mike Cassidy 98 pts. 11,170
• 4. Bletchley Park 96 pts. 11,167
• 5. jamiexq 95 pts. 11,165
• 6. spvincent 93 pts. 11,163
• 7. LociOiling 92 pts. 11,158
• 8. mberna00 91 pts. 11,156
• 9. retiredmichael 89 pts. 11,153
• 10. gmn 88 pts. 11,148

Comments

[v_mulligan]

I'll mention that to the Foldit developers at our weekly meeting tomorrow. It could be a good feature to have.

[viosca]

This is probably a bit afield of this topic, but are there animals that exhibit immunity/resistance to the virus? If so, do we know what their strategy is? Thanks!

[retiredmichael]

just to confirm, have been looking through the team shares and the high scores have all drifted out of the pocket.

[LociOiling]

@jeff101, it looks like the "cap loop" is segments 122-130. If you orient the cap loop at the top as shown in the image, the binding pocket is the mostly empty area below it. The lower edge of the pocket is something like segments 14-23.

[Anfinsen_slept_here]

Sorry if this is snarky. But why the British spelling? Is Washington State that close to British Columbia that they use the Queen's English?

[spmm]

http://mbio.asm.org/content/5/1/e00862-13.full.pdf This open access paper suggests that there is a small region which is conserved and very similar across the filovirus family. I was trying to work out what popped the cap off as well.

[Bautho]

I found some more things, which could be good to know:

1) "delete" function of residues is disabled at some point during the game:
– if you delete both the two residues at one terminus and reinsert them, you cannot delete them again (but you can still insert residues, and undoing and resetting the whole structure will enable it again).
– if you delete all 4 deletable residues, you cannot 'insert' anything to the remaining single residue

2) saved solutions usually can be loaded as a guide (which can be useful to rebuild the peptide in other starting conformations of the ebola protein), but sometimes Foldit crashes completely
– the solution with disabled delete function also caused a crash, maybe there is the point why the game cannot load it as guide

[Seagat2011]

The human body already creates antibodies to fight off the Ebola infection but Ebola dehydrates the body before it can complete this effort.

[v_mulligan]

I'm Canadian. I haven't quite mastered the simplified American spellings yet – all those "c" to "s" mutations and "u" deletions…

[v_mulligan]

Yes, exactly. Altering the rate at which the virus infects cells can give the immune system time to fight off the infection.