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

The ability of tr,alpha,alpha-di-n-alkyl glycines with linear and cyclic al kyl side chains to stabilize helical conformations has been compared rasing a model heptapeptide sequence. The conformations of five synthetic heptape ptides (Boc-Val-Ala-Leu-Xxx-Val-Ala-Leu-OMe, Xxx = Ac(8)c, Ac(7)c, Aib, Dpg , and Deg, where Ac(8)c = 1-aminocycloactane-1-carboxylic acid, Ac(7)c =1-a minocycloheptane-1-carboxylic acid; Aib = alpha-aminoisobutyric acid, Dpg = alpha,alpha-di-n-propyl glycine, Deg = alpha,alpha-di-n-ethyl glycine) hav e been investigated. In crystals, helical conformations have been demonstra ted by x-ray crystallography for the peptides, R-Val-Ala-Leu-Dpg-Val-Ala-Le u-OMe, (R = Boc and acetyl). Solution conformations of the five peptides ha ve been studied by H-1-nmr. In the apolar solvent CDCl3, all five peptides favor helical conformations in which the NH groups of residues 3-7 are shie lded from the solvent Successive NiH <----> Ni+1H nuclear Overhauser effect s over the length of the sequence support a major population of continuous helical conformations. Solvent titration experiments in mixtures of CDCl3/D MSO provide evidence for solvent-dependent conformational transitions that are more pronounced for the Deg and Dpg peptides. Solvent-dependent chemica l shift variations and temperature coefficients in DMSO suggest that the co nformational distributions in title Deg/Dpg peptides are distinctly differe nt from the Aib/Ac(n)c peptides in a strongly solvating medium. Nuclear Ove rhauser effects provide additional evidence for the population of extended backbone conformations in the Dpg peptide, while a significant residual pop ulation of helical conformations is still detectable in the isomeric Ac(7)c peptide in DMSO. (C) 2000 John Wiley & Sons, Inc.