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

Conformational studies on the synthetic 11-aa peptide t-butoxy-carbonyl (Boc)-Val-Ala-Phe-alpha-aminoisobutyric acid (Aib)-(R)-beta(3)-homovaline (betaVal)-(S)-beta(3)-homophenylalanine (betaPhe)-Aib-Val-Ala-Phe-Aib-methyl ester (OMe) (peptide 1; betaVal and betaPhe are beta amino acids generated by homologation of the corresponding L-residues) establish that insertion of two consecutive beta 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 130 segment, helical hydrogen-bonded rings are expanded. A C-15 hydrogen bond for the alphabetabeta segment and two C-14 hydrogen bonds for the alphaalphabeta or betaalphaalpha segments have been characterized. The following conformational angles were determined from the crystal structure for the beta residues: betaVal-5 (phi = -126degrees, theta = 76degrees, and psi = -124) and betaPhe-6 (phi = -88degrees, theta = 80degrees, and psi = -118). The N terminus of the peptide is partially unfolded in crystals. The 500-MHz H-1-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.