The Preferred Conformation of (alphaMe)Trp peptides

The two Z-L-Ala-DL-(xMe)Trp-NH2 diastereomeric dipeptides were synthesized from (Z-L-Ala)2O and H-DL-(xMe)Trp-NH2. The latter racemate, prepared by phase-transfer catalyzed alkylation of the Nalpha-benzylidene derivative of alanine amide followed by acidic hydrolysis of the resulting Schiff base, was characterized by X-ray diffraction. The molecular and crystal structure of Z-L-Ala-L-(alphaMe)Trp-NH2, separated from its diastereomer by silica-gel column chromatography, was determined by X-ray diffraction analysis. Both independent molecules in the asymmetric unit of the dipeptide adopt a type-II beta-bend conformation. However, only the more regularly folded conformation of molecule B is stabilized by a 1<-4 C=O...H--N intramolecular H bond. The present results indicate that: (i) the Calpha-methylated (alpha Me)Trp residue is a strong beta-bend and helix former, and (ii) the relationship between (alphaMe)Trp chirality and helix screw sense tends to be opposite to that of protein amino acids. The implications for the use of the (alphaMe)Trp residue in designing conformationally restricted analogs of bioactive peptides are briefly discussed.