LINEAR OLIGOPEPTIDES .275. REVERSE RELATIONSHIP BETWEEN ALPHA-CARBON CHIRALITY AND HELIX HANDEDNESS IN (ALPHA-ME)PHE PEPTIDES

The crystal-state preferred conformations of two tripeptides, one tetrapeptide, and one pentapeptide, each containing a single residue of the chiral. C(alpha,alpha)-disubstituted glycine C(alpha)-methyl, C(alpha)-benzylglycine [(alphaMe)Phe], have been determined by X-ray diffraction. The tripeptides are Z-L-(alphaMe)Phe-(Aib)2-OH dihydrate and Z-Aib-D-(alphaMe)Phe-Aib-OtBu, the tetrapeptide is Z-(Aib)2-D-(alphaMe)Phe-Aib-OtBu. and the pentapeptide is pBrBz-(Aib)2-DL-(alphaMe)Phe-(Aib)2-OtBu. While the two tripeptides are folded in a beta-bend conformation, two such conformations are consecutively formed by the tetrapeptide. The pentapeptide adopts a regular 3(10)-helix promoted by three consecutive beta-bends. This study confirms the strong propensity of short peptides containing C(alpha)-methylated alpha-aminoacids to fold into beta-bends and 3(10)-helical structures. Since Aib is achiral, the handedness of the observed bends and helices is dictated by the presence of the (alphaMe)Phe residue. In general. we have found that the relationship between (alphaMe)Phe chirality and helix handedness is opposite to that exhibited by protein aminoacids. A comparison with the preferred conformation of other extensively investigated C(alpha)-methylated aminoacids is made.