Impact of Backbone Pattern and Residue Substitution on Helicity in ?/?/?-Peptides.

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

SUBMITTER: Shin YH 

PROVIDER: S-EPMC5986291 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature