αβ hybrid peptides: A polypeptide helix with a central segment containing two consecutive β-amino acid residues

Abstract

Conformational studies on the synthetic 11-aa peptide t-butoxycarbonyl (Boc)-Val-Ala-Phe-α-aminoisobutyric acid (Aib)-(R)-β³-homovaline (βVal)-(S)-β³-homophenylalanine (βPhe)-Aib-Val-Ala- Phe-Aib-methyl ester (OMe) (peptide 1; βVal and βPhe are β amino acids generated by homologation of the corresponding L-residues) establish that insertion of two consecutive β residues into a polypeptide helix can be accomplished without significant structural distortion. Crystal-structure analysis reveals a continuous helical conformation encompassing the segment of residues 2-10 of peptide 1. At the site of insertion of the ββ segment, helical hydrogen-bonded rings are expanded. A C₁₅ hydrogen bond for the αββ segment and two C₁₄ hydrogen bonds for the ααβ or βαα segments have been characterized. The following conformational angles were determined from the crystal structure for the β residues: βVal-5 (Φ = -126°, θ 76°, and Ψ = -124) and βPhe-6 (Φ= -88°, θ = 80°, and Ψ = -118). The N terminus of the peptide is partially unfolded in crystals. The 500-MHz ¹H-NMR studies establish a continuous helix over the entire length of the peptide in CDCl₃ solution, as evidenced by diagnostic nuclear Overhauser effects. The presence of seven intramolecular hydrogen bonds is also established by using solvent dependence of NH chemical shifts.