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

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 = Ac 8 c, Ac 7 c, Aib, Dpg, and Deg, where Ac 8 c = 1‐aminocyclooctane‐1‐carboxylic acid, Ac 7 c = 1‐aminocycloheptane‐1‐carboxylic acid, Aib = α‐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 1 H‐nmr. In the apolar solvent CDCl 3 , all five peptides favor helical conformations in which the NH groups of residues 3–7 are shielded from the solvent. Successive N i H ↔ N i +1 H nuclear Overhauser effects over the length of the sequence support a major population of continuous helical conformations. Solvent titration experiments in mixtures of CDCl 3 /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 n c 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 Ac 7 c peptide in DMSO. © 2000 John Wiley & Sons, Inc. Biopoly 53: 84–98, 2000