Conformational preferences of proline analogues with a fused benzene ring

摘要

The intrinsic conformational preferences of indoline-2-carboxylic acid (Inc) and its R-methylated derivativeud(RMeInc) have been investigated using quantum mechanical calculations. Specifically, the behavior of theirudN-acetyl-N′-methylamide derivatives, Ac-L-Inc-NHMe and Ac-L-RMeInc-NHMe, has been explored at theudB3LYP/6-31+G(d,p) level. Such amino acids are analogues of proline and (R-methyl)proline, respectively,udbearing a benzene ring fused to the Cγ-Cδ bond of the five-membered pyrrolidine ring. The additional aromaticudgroup has been shown to significantly restrict the conformational space available to these residues by reducingudthe flexibility of both the five-membered cycle and the peptide backbone. The fused benzene ring also playsuda critical role in determining the cis-trans arrangement of the amide bond involving the pyrrolidine nitrogen,udwhich is also modulated by the presence of the R-methyl group in the RMeInc derivative. Furthermore, theudinfluence of the environment on the conformational propensities of these compounds has been evaluated byudusing both a self-consistent reaction field model and a recently developed interface in a hybrid QM/MMudscheme, in which the solvent molecules are treated explicitly with classical mechanics while the solute isuddescribed by quantum mechanics at the density functional theory level.