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1117: Ultra-compact 17-residue Marburg virus inhibitor
Status: Closed

Summary

Name: 1117: Ultra-compact 17-residue Marburg virus inhibitor
Status: Closed
Created: 07/21/2015
Points: 100
Expired: 07/30/2015 - 23:00
Difficulty: Intermediate
Description: This is the third in our series of Marburg inhibitor peptide puzzles. 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.)
Categories: Design, Overall

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Comments

v_mulligan's picture
User offline. Last seen 8 weeks 21 hours ago. Offline
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Expiry date change

Sorry about that, folks -- I meant to have this expire on the 30th, not the 28th, to space things out a bit with the other puzzles. The expiry date has been updated.

brow42's picture
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Joined: 09/19/2011
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Bridge Stability

In this very small puzzle (I have never satisfied a core filter with such a peptide) won't the bridges be exposed and easily attacked by reducing agents in the blood and CSF? I suppose I can *try* to stuff the bridges in the middle of the core, but again, I probably don't have a core, at least, how the filter defines it.

bkoep's picture
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Oxidizing environments

The blood and spinal fluid are oxidizing environments, so we don't need to worry about the disulfide bonds being reduced. Any reduced cysteine pairs would quickly oxidize.

brow42's picture
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Fragment Filter

It seems unlikely that loops will fold in a tiny knot the same way as globular proteins. Perhaps if you are going to make many different peptides in the laboratory, you could compare the effectiveness of the fragment filter on this puzzle. It would be great to turn this off if it is not helping.

bkoep's picture
User offline. Last seen 13 hours 53 min ago. Offline
Joined: 11/15/2012
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Good point

You make a good point that heuristics like the Fragment Filter probably don't apply equally to both large globular proteins and small peptides. Unfortunately, it may be the case that the Fragment Filter is more important here.

In fact, someone in the Baker Lab has recently done an experiment similar to the one you propose. They found that for small disulfide-bonded proteins, fragment quality is actually a powerful predictor of protein stability in the lab.

One possibility is that "bad" (i.e. rarely observed) fragments perhaps represent subtly strained conformations of the backbone. A large protein may be able to compensate for this strain by making a lot of favorable interactions elsewhere. A small protein would simply adopt another conformation with less strained backbone.

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Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
Supported by: DARPA, NSF, NIH, HHMI, Amazon, Microsoft, Adobe, RosettaCommons