Is the Backbone Conformation of C-alpha-Methyl Proline Restricted to a Single Region?

Ca-Methyl-l-proline, or l- (aMe)Pro, is probably the most conformationally constrained a-amino acid. In particular, its w and f torsion angles are restricted to about 180 and 608, respectively, and only three ranges of values are theoretically available for y in mono- or longer peptides, namely, about 308 (cis’, 310/a-helical structure), 608 (inverse g turn), or 1408 (trans’, polyACHTUNGTRENUNG(l-Pro)n II structure). In this work, we examined the tendency of a number of Na-acyl dipeptide N’-alkylamides of the type RCO-(aMe)Pro- Xxx-NHR’ or RCO-Xxx-(aMe)Pro- NHR’, in which Xxx is l (or d)-Ala, Aib (a-aminoisoburyric acid), or l (or d)-(aMe)Pro, long enough to fold into intramolecularly hydrogen-bonded g or b turns. The results are compared with those obtained for the corresponding dipeptides based on Pro, a well-known turn-forming residue. For the crystalstate 3D-structural analysis we used Xray diffraction, whereas our solution conformational analysis was heavily based on the FTIR absorption and 1H and 13C NMR spectroscopy techniques. We conclude that (aMe)Pro is able to explore both trans’ and cis’ y areas of the conformational space, but in (aMe)Pro the latter is overwhelmingly more populated, in marked contrast to the Pro preference. This finding is a clear indication that in (aMe)Pro the major 3D-structural determinant is the Ca-methyl group. The circular dichroism (CD) signature of a peptide type III’ b-turn conformation is also proposed.