Abstract by Kimberlee Stern
Chemistry and Biochemistry
Folding of a helix bundle is stabilized by a solvent exposed non-covalent interaction
α-helical coiled coils (or helix bundles) are among the most extensively characterized tertiary/quaternary structural motifs within proteins. Folding of these helix bundles is driven by burial of non-polar amino acids at the interhelical interface; these non-polar residues typically occupy a and d positions within the repeating abcdefg heptad sequence. In contrast, many helix-bundle design efforts assume that substitutions at solvent-exposed b, c, and f positions should have minimal structural consequences. Our results challenge this assumption: here we show that solvent-exposed f-position residue14 can facilitate a stabilizing long-range synergistic interaction involving a b-position Glu10 (i.e., i–4 relative to residue 14) and c-position Lys18 (i.e., i+4) within a well-characterized trimeric helix bundle. The extent of stabilization associated with the Glu10-Lys18 pair depends primarily on the presence of a side-chain hydrogen-bond donor at residue 14. The non-polar or hydrophobic character of residue plays a smaller but still significant role. These results suggest the need to consider substituion at these positions in helix design.