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1073: Marburg Binder Design with Disulfides

Closed since over 7 years ago

Intermediate Overall Design


April 09, 2015
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Marburgvirus is a close relative of ebolavirus, and is similarly prone to epidemics in humans and primates. This is a design puzzle with 37 residues, near the interface of a target glycoprotein from the Marburg virus. At the binding site of the Marburg protein, there is already a beta hairpin derived from a human antibody. Build a scaffold around the starting design that will fold up properly and stabilize the binding hairpin! There are strong constraints to keep the hairpin residues in place, and you may not mutate residues at the interface. Players will receive an (extremely) large bonus for making up to 2 disulfide bonds. Remember to share your favorite designs using the Share with Scientist tool, even if those are not your best-scoring solutions!

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Susume Lv 1

The hairpin you have given us does not follow the chirality of the large majority of native 5-residue hairpins, as described in the beta-beta rule of the ideal design paper. This may make it hard to come up with a peptide that will fold as intended; that loop will be trying to turn the other way.

v_mulligan Staff Lv 1

It's true that some of the loop residues are in odd conformations, but this is what was observed in the crystal structure of the antibody-viral glycoprotein complex. Although strained conformations are best avoided in totally de novo designs, we're hopeful that, given that this is a conformation that has been observed experimentally, we can reproduce it in artificial designs. But that's a good observation!

(As an aside, we are considering variant designs in which we use unnatural amino acid residues with reversed chirality at some of these loop positions. Unfortunately, Foldit is not currently set up to allow us to give you a puzzle with mirror-image amino acids, but we might try that at some point…)

LociOiling Lv 1

Late to the chase, but segment 257 has type "M" or "ligand", which throws off many recipes. Looks like a normal segment to me, is this the intention?

LociOiling Lv 1

I have another version of the same solution that shows 257 as a normal segment. I think it's the parent of one of the type "M" ones, so maybe it has something to do with sharing. Time to check feedbacks.

v_mulligan Staff Lv 1

Curious – it was a normal segment in the puzzle setup, but I am seeing some funny business in some, but not all, of the PDB files for some of the results. I'm not sure what caused the problem, but if we can track it down, we will.