Impact of Backbone Pattern and Residue Substitution on Helicity in α/β/γ-Peptides.

Abstract

We have evaluated the impact of changes in the chemical structure of peptidic oligomers containing α-, β-, and γ-amino acid residues (α/β/γ-peptides) on the propensities of these oligomers to adopt helical conformations in aqueous and alcoholic solutions. These studies were inspired by our previous discovery that α/β/γ-peptides containing a regular αγααβα hexad repeat adopt an α-helix-like conformation in which the β and γ residues are aligned in a stripe along one side, and the remainder of the helix surface is defined by the α residues. This helix was found to be most stable when the β and γ residues were rigidified with specific cyclic constraints. Relaxation of the β residue constraints caused profound conformational destabilization, but relaxation of the γ residue constraints led to only a moderate drop in helicity. The new work more broadly characterizes the effect of γ residue substitution on helix stability, based on circular dichroism and two-dimensional NMR measurements. We find that even a fully unsubstituted γ residue (derived from γ-aminobutyric acid) supports a moderate helical propensity, which is surprising in light of the strong destabilizing effect of glycine residues on α-helix stability. Additional studies examine the effects of altering sequence in terms of amino acid type, by comparing a prototype with the αγααβα hexad pattern to isomers with irregular arrangements of the α, β, and γ residues along the backbone. The data indicate that the strong helix-forming propensity previously discovered for α/β/γ-peptide 12-mers is retained when sequence is varied, with small variations detected across diverse α-β-γ placements. These structural findings suggest that α/β/γ-peptide scaffolds represent versatile scaffolds for the design of peptidic foldamers that display specific functions.