Feedback on Marburg puzzle 1108 ("Compact 37-Residue Marburg Virus Inhibitor Design")
Hi, folks. Thanks to all who played the latest Marburg puzzle. We have looked over the results, and it looks like the scoring was promoting some of what we wanted to see, though I think that maybe we should have given a bigger bonus for creating a core (and maybe required a few more residues in the core). While the top-scoring designs looked pretty good, some of the most interesting were, once again, in the "shared with scientist" category. Two in particular stood out:
Susume of Anthropic Dreams created a very interesting-looking sandwich of beta-strands, with a great "leapfrog" arrangement of disulfide bonds (cys3-cys21, cys7-cys33). Importantly, all strands contributed hydrophobic residues to the core, and there were no voids in the core, so it's a plausible-looking fold for presenting the antibody loop. My one criticism is that this only makes one additional charge-charge interaction with the target and one additional hydrophobic interaction, but on the other hand, putting the effort into having a nice, stable fold might be a good strategy.
LociOiling from the Beta Folders went with a nice, classic helix packing against a three-stranded sheet. The helix is very nice and plausible, with one clearly hydrophobic face in which every turn either presents a hydrophobic amino acid residue, or is involved in a disulfide bond. Again, we have a nice "leapfrog" disulfide pattern of the sort often seen in small peptides in the natural world. In this case, my only criticism is that the third strand isn't doing much to contribute to the fold or to binding (with the exception of a single valine that's making a hydrophobic interaction with the target). Still, it's conceivable that this would bind just fine if it were truncated down to a helix and a two-stranded sheet...
...Which is a good segue into our next puzzle: a smaller, 25-residue Marburg binder. Why smaller? Stay tuned for the new puzzle for more information!