Is the backbone conformation of C-alpha-methyl proline restricted to a single region?

C-alpha-Methyl-L-proline, or L-(alpha Me)Pro, is probably the most conformationally constrained alpha-amino acid. In particular, its omega and phi torsion angles are restricted to about 180 and -60 degrees, respectively, and only three ranges of values arc theoretically available for psi in mono- or longer peptides, namely, about -30 degrees (cis', 3(10)/alpha-helical structure), 60 degrees (inverse gamma turn), or 140 degrees (trans', poly(L-Pro)(n) II structure). In this work, we examined the tendency of a number of N-alpha-acyl dipeptide N'-alkylamides of the type RCO-(alpha Me)Pro-Xxx-NHR' or RCO-Xxx-(alpha Me)Pro-NHR', in which Xxx is L (or D)-Ala, Aib (alpha-aminoisoburyric acid), or L (or D)-(alpha Me)Pro, long enough to fold into intramolecularly hydrogen-bonded gamma or beta turns. The results are compared with those obtained for the corresponding dipeptides based on Pro, a well-known turn-forming residue. For the crystal-state 3D-structural analysis we used X-ray diffraction, whereas our solution conformational analysis was heavily based on the FTIR absorption and H-1 and C-13 NMR spectroscopy techniques. We conclude that (alpha Me)Pro is able to explore both trans' and cis' psi areas of the conformational space, but in (alpha Me)Pro the latter is overwhelmingly more populated, in marked contrast to the Pro preference. This finding is a clear indication that in (alpha Me)Pro the major 3D-structural determinant is the C-alpha-methyl group. The circular dichroism (CD) signature of a peptide type III' beta-turn conformation is also proposed.