Strong Contributions from Vertical Triads to Helix-Partner Preferences in Parallel Coiled Coils

Pairing preferences in heterodimeric coiled coils are
determined
by complementarities among side chains that pack against one another
at the helix–helix interface. However, relationships between
dimer stability and interfacial residue identity are not fully understood.
In the context of the “knobs-into-holes” (KIH) packing
pattern, one can identify two classes of interactions between side
chains from different helices: “lateral”, in which a
line connecting the adjacent side chains is perpendicular to the helix
axes, and “vertical”, in which the connecting line is
parallel to the helix axes. We have previously analyzed vertical interactions
in antiparallel coiled coils and found that one type of triad constellation
(a′–a–a′) exerts a strong
effect on pairing preferences, while the other type of triad (d′–d–d′) has relatively little
impact on pairing tendencies. Here, we ask whether vertical interactions
(d′–a–d′) influence pairing
in parallel coiled-coil dimers. Our results indicate
that vertical interactions can exert a substantial impact on pairing
specificity, and that the influence of the d′–a–d′ triad depends on the lateral a′ contact
within the local KIH motif. Structure-informed bioinformatic analyses
of protein sequences reveal trends consistent with the thermodynamic
data derived from our experimental model system in suggesting that
heterotriads involving Leu and Ile are preferred over homotriads involving
Leu and Ile.