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1121b: Ultra-compact 17-residue Marburg glycoprotein inhibitor design 2

Closed since over 10 years ago

Summary

Created: August 04, 2015
Expires: August 12, 2015 at 23:00 UTC
Max points: 100

Description

This is a slight variant on the last 17-residue Marburg design puzzle. Based on the results from that puzzle, we've changed the following:

-- We're going to make the core existence filter slightly more stringent, to encourage having a few more buried residues.

-- Because this is so short, we're going to let you design more positions. The puzzle starts with four residues from an glycoprotein/antibody co-crystal structure, but only two of these that are most deeply buried in the target are fixed. You can mutate the other two if you so wish.

-- Similarly, only those two residues are tethered to lie in the pocket, now. The rest of the residues are fully flexible, so you can alter the backbone as you see fit.

-- To improve the responsiveness of the puzzle, we've trimmed the target back a bit more, so that you just see the part near the binding pocket. You can improve the responsiveness further by disabling filters during manipulation.

We'd like you to design a 17-residue peptide that's able to inhibit the Marburg glycoprotein, a viral surface protein that allows the Marburg virus to infect cells. Seventeen residues might seem quite small, but smaller size can make it easier for a peptide to pass through barriers, such as the gut-blood barrier or the blood-brain barrier, and can also make it less likely to trigger an immune response. It's also quite easy to synthesize a peptide this small, which can mean both that we can make large amounts and that we can include unnatural amino acids or other chemical modifications that would not be possible in a protein that's expressed in bacteria or yeast, but which might aid function or stability. The flip side, though, is that it's more challenging to design something that folds well and binds with high affinity and specificity in this small size range -- but that's the challenge!

We'd like nice, compact designs that bury a sizable hydrophobic core, have no voids in their cores, have lots of secondary structure (helices and sheets) and have good disulfide bonding patterns. Players should also try to maximize contacts (especially hydrophobic contacts) between the peptide and the target. We suspect that designs with a helix lying across a two-standed sheet will work best in this puzzle, but that's not carved in stone. We're giving you a bonus for forming at least two disulfide bonds, as well as a strong bonus for making a good hydrophobic core. This puzzle also uses the fragment filter, so make sure that your designed segments have good fragment quality! (The fragment filter will unfortunately penalize the target as well as the design, but that affects everyone equally and gives no one an advantage.)