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835: SOD1 Hotspot

Closed since about 12 years ago

Intermediate Overall Design

Summary

Created
January 17, 2014
Expires
Max points
100
Description

Mutations in the gene encoding the SOD1 protein cause a subset of cases of amyotrophic lateral sclerosis, or Lou Gehrig's disease. There is some evidence that the two SOD1 subunits in the dimer separate as part of the aggregation process, so a molecule that is able to "glue" the dimer together could help to slow or halt the molecular events that lead to the disease. As a starting point for designing such a "glue", we'd like you to find good places at the interface between the SOD1 subunits to place a small, three-residue fragment. In designing the sequence of this fragment, keep in mind that hydrophobic interactions (interactions with orange residues) are much more likely to give high affinity and specificity than polar interactions (interactions with blue residues), so we recommend focusing on placing hydrophobic side-chains in the cleft between the subunits. Good luck!

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Comments

v_mulligan Lv 1

One player pointed out that SOD1 is a metalloprotein (i.e. it has metal atoms as part of its structure – one copper and one zinc per subunit). This is true, though they're not shown in this puzzle. I stripped out the metals for this puzzle because they're far from the region where we want our peptide to bind (the dimer interface), and because the puzzle would have required a little bit of extra setup on our part in order to make sure that Foldit didn't choke on the metals. The bottom line is that I was being a little bit lazy by leaving them out, but they wouldn't make a difference in this case!

bkoep Staff Lv 1

It's okay if the terminals of your small peptide are buried or directed toward the target protein. These peptides might be hard to map directly onto a larger protein, but such high-scoring hotspots are still very informative.

v_mulligan Lv 1

That's a good question, though. Since I will be extending the "stub", I will ultimately need exposed termini – but bkoep is correct; you don't need to worry about it. The most important thing for this puzzle is getting the side-chains to dock well at the SOD1 dimer interface. I can tweak the backbone after the fact for subsequent design, so designs with buried termini are still perfectly fine.