Generation and analysis of the conformational potential energy surfaces of N-acetyl-N-methyl-L-alanine-N′-methylamide.: An exploratory ab initio study

N-methylation is a naturally occurring modification in small peptides, e.g. antibiotics that can effect the conformational preferences of the molecule as well as the ease of trans to cis isomerization of the involved peptide bond. In the present exploratory study we have calculated the potential energy surface of both N-acetyl-L-alanine-N'-methylamide and N-acetyl-N-methyl-L-alanine-N'-methylamide at the RHF/3-21G level of theory with a cis-trans or with a trans-trans peptide conformation. With respect to the non-methylated model system our results indicate that N-methylation reduces the number of observable backbone conformers in both amide configurations. The effect of methylation on the ease of trans to cis isomerization was assessed by calculating the energetics of the corresponding transition structures. An increase in the activation energies of the trans to cis isomerization of the relevant peptide bond was observed for the N-methylated moiety. (C) 2003 Elsevier Science B.V. All rights reserved.