Comparison of helix-stabilizing effects of α,α-dialkyl glycines with linear and cycloalkyl side chains

Abstract

The ability of α,α-di-n-alkyl glycines with linear and cyclic alkyl side chains to stabilize helical conformations has been compared using a model heptapeptide sequence. The conformations of five synthetic heptapeptides (Boc-Val-Ala-Leu-Xxx-Val-Ala-Leu-OMe, Xxx = Ac₈c, Ac₇c, Aib, Dpg, and Deg, where Ac₈c = 1-aminocyclooctane-1-carboxylic acid, Ac₇c = 1-aminocycloheptane-1-carboxylic acid, Aib = -aminoisobutyric acid, Dpg = α,α-di-n-propyl glycine, Deg = α,α-di-n-ethyl glycine) have been investigated. In crystals, helical conformations have been demonstrated by x-ray crystallography for the peptides, R-Val-Ala-Leu-Dpg-Val-Ala-Leu-OMe, (R = Boc and acetyl). Solution conformations of the five peptides have been studied by ¹H-nmr. In the apolar solvent CDCl₃, all five peptides favor helical conformations in which the NH groups of residues 3-7 are shielded from the solvent. Successive N_iH ↔ N_i+1H nuclear Overhauser effects over the length of the sequence support a major population of continuous helical conformations. Solvent titration experiments in mixtures of CDCl₃/DMSO provide evidence for solvent-dependent conformational transitions that are more pronounced for the Deg and Dpg peptides. Solvent-dependent chemical shift variations and temperature coefficients in DMSO suggest that the conformational distributions in the Deg/Dpg peptides are distinctly different from the Aib/Ac_nc peptides in a strongly solvating medium. Nuclear Overhauser effects provide additional evidence for the population of extended backbone conformations in the Dpg peptide, while a significant residual population of helical conformations is still detectable in the isomeric Ac₇c peptide in DMSO.