N‐Methyl peptides

Abstract

The natural occurrence of N‐methyl peptides in various plant metabolites has made N‐methylation a subtle and attractive possible modification for structure‐activity relationship studies of endogeneous peptides. However, little is known about the conformational specificity induced by the N‐methylation of a given peptide, and particularly concerning the β‐turn conformation. A spectroscopic investigation (i.r., n.m.r., CD) and X‐ray diffraction experiments have been carried out on tBuCO‐X‐Me‐Y‐NHMe blocked dipeptides (X = Gly, L‐Ala, L‐Pro, and Y = Gly, and L‐ or D‐Ala, Leu, Phe) with reference to the homologous desmethylated species. The influence of the N‐methylation on conformation depends to a large extent on the chirality of the X and Y residues. Homochiral sequences are the most affected, with a strong preference for the βVI‐folded conformation containing a middle cis amide bond. Heterochiral sequences are essentially unaffected and retain the βII‐folded conformation with a trans middle amide bond. Glycine‐containing sequences undergo a more complex perturbation according to the X or Y position of the Gly residue. The available data for larger N‐methyl peptides are consistent with our observations, suggesting that these simple dipeptides well reflect the conformational perturbations induced by N‐methylation on the β‐turn conformation.