Is the Backbone Conformation of Cα‐Methyl Proline Restricted to a Single Region?

Cα‐Methyl‐L‐proline, or L‐(αMe)Pro, is probably the most conformationally constrained α‐amino acid. In particular, its ω and ϕ torsion angles are restricted to about 180 and −60°, respectively, and only three ranges of values are theoretically available for ψ in mono‐ or longer peptides, namely, about −30° (cis′, 310/α‐helical structure), 60° (inverse γ turn), or 140° (trans′, poly(L‐Pro)n II structure). In this work, we examined the tendency of a number of Nα‐acyl dipeptide N′‐alkylamides of the type RCO‐(αMe)Pro‐Xxx‐NHR′ or RCO‐Xxx‐(αMe)Pro‐NHR′, in which Xxx is L (or D)‐Ala, Aib (α‐aminoisoburyric acid), or L (or D)‐(αMe)Pro, long enough to fold into intramolecularly hydrogen‐bonded γ or β 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 1H and 13C NMR spectroscopy techniques. We conclude that (αMe)Pro is able to explore both trans′ and cis′ ψ areas of the conformational space, but in (αMe)Pro the latter is overwhelmingly more populated, in marked contrast to the Pro preference. This finding is a clear indication that in (αMe)Pro the major 3D‐structural determinant is the Cα‐methyl group. The circular dichroism (CD) signature of a peptide type III′ β‐turn conformation is also proposed. Super restricted! Cα‐Methyl proline, with its ω and ϕ backbone torsion angles blocked to about 180 and −60°, respectively, differs remarkably from proline in that it overwhelmingly prefers a single region of the conformational space. The Cα‐methyl group seems to dominate its 3D structural choice (see figure).