Dehydrophenylalanine zippers: strong helix-helix clamping through a network of weak interactions

Abstract

A decapeptide Boc-L-Ala-(ΔPhe)₄-L-Ala-(ΔPhe)₃-Gly-OMe (Peptide I) was synthesized to study the preferred screw sense of consecutive α,β-dehydrophenylalanine (ΔPhe) residues. Crystallographic and CD studies suggest that, despite the presence of two L-Ala residues in the sequence, the decapeptide does not have a preferred screw sense. The peptide crystallizes with two conformers per asymmetric unit, one of them a slightly distorted right-handed 3₁₀-helix (X) and the other a left-handed 3₁₀-helix (Y) with X and Y being antiparallel to each other. An unanticipated and interesting observation is that in the solid state, the two shape-complement molecules self-assemble and interact with an extensive network of C-H···O hydrogen bonds and π-π interactions, directed laterally to the helix axis with amazing regularity. Here, we present an atomic resolution picture of the weak interaction mediated mutual recognition of two secondary structural elements and its possible implication in understanding the specific folding of the hydrophobic core of globular proteins and exploitation in future work on de novo design.