Helix Nucleation via Hydrocarbon Cross-link Mimicking N-capping Box

Abstract

The N-capping box is a well-known helix-stabilizing motif with a distinct reciprocal backbone-side chain hydrogen-bonding arrangement at the N-terminus of helices. This unique N-terminal flanking motif consists of a hydrogen-bonded cycle of four amino acid residues in which the backbone amide of the N3 residue forms a hydrogen bond with the side chain of the Ncap residue, and reciprocally, the side chain of the N3 accepts a hydrogen from the Ncap amide. In this study, as a new helix-stabilizing strategy, we examined a metathesis-based cross-linking system that mimics the hydrogen bond between the Ncap amide and the side chain of the N3 at the N-terminus. Using this new system, we prepared two alanine/lysine-based model peptides and analyzed its impact on helix stabilization. We found that a 16-membered macrocycle incorporated by ring-closing metathesis effectively induces and stabilizes helical conformations of the given model sequence.