C-alpha-methyl proline: A unique example of split personality

Methylation at the C-alpha-position of a Pro residue was expected to lock the preceding tertiary amide (omega) torsion angle of the resulting (alpha Me)Pro to the trans disposition and to restrict the, surface to the single region where the 3(10)/alpha-helices are found (in this five-membered ring residue is severely constrained to about +/- 65 degrees by its cyclic nature). The results of the present X-ray diffraction work on a selected set of four N-alpha-blocked, (alpha Me)Pro-containing, dipeptide N'-alkylamides clearly show that, although the region of the conformational map largely preferred by (alpha Me)Pro would indeed be that typical of 3(10)/alpha-helices, the semi-extended [type-II poly(Pro)(n) helix] region can also be explored by this extremely sterically demanding C-alpha-tetrasubstituted alpha-amino acid. In addition, the known high propensity for beta-turn formation of the Pro residue is further enhanced in peptides based on its C-alpha-methylated derivative.