Prerequisites for Stabilizing Long-Range Synergistic Interactions among b -, c -, and f -Residues in Coiled Coils.

Coiled coils are among the most abundant tertiary and quaternary structures found in proteins. A growing body of evidence suggests that long-range synergistic interactions among solvent-exposed residues can contribute substantially to coiled-coil conformational stability, but our understanding of the key sequence and structural prerequisites of this effect is still developing. Here, we show that the strength of synergistic interaction involving a b -position Glu ( i ), an f -position Tyr ( i + 4), and a c -position Lys ( i + 8) depends on the identity of the f -position residue, the length and stability of the coiled coil, and its oligomerization stoichiometry/surface accessibility. Combined with previous observations, these results map out predictable sequence- and structure-based criteria for enhancing coiled-coil stability by up to -0.58 kcal/mol per monomer (or -2.32 kcal/mol per coiled-coil tetramer). Our observations expand the available tools for enhancing coiled coil stability by sequence variation at solvent-exposed b -, c -, and f -positions and suggest the need to exercise care in the choice of substitutions at these positions for application-specific purposes.