The intrinsic conformational preferences of indoline-2-carboxylic acid (Inc) and its α-methylated derivative (αMeInc) have been investigated using quantum mechanical calculations. Specifically, the behavior of their N-acetyl-N′-methylamide derivatives, Ac-l-Inc-NHMe and Ac-l-αMeInc-NHMe, has been explored at the B3LYP/6-31+G(d,p) level. Such amino acids are analogues of proline and (α-methyl)proline, respectively, bearing a benzene ring fused to the Cγ−Cδ bond of the five-membered pyrrolidine ring. The additional aromatic group has been shown to significantly restrict the conformational space available to these residues by reducing the flexibility of both the five-membered cycle and the peptide backbone. The fused benzene ring also plays a critical role in determining the cis−trans arrangement of the amide bond involving the pyrrolidine nitrogen, which is also modulated by the presence of the α-methyl group in the αMeInc derivative. Furthermore, the influence of the environment on the conformational propensities of these compounds has been evaluated by using both a self-consistent reaction field model and a recently developed interface in a hybrid QM/MM scheme, in which the solvent molecules are treated explicitly with classical mechanics while the solute is described by quantum mechanics at the density functional theory level.

Financial support from Ministerio de Ciencia e Innovación - FEDER (project CTQ2007-62245), Gobierno de Aragón (research group E40, predoctoral fellowship to J.G.W.), Caja de Ahorros Inmaculada (Programa Europa, travel grant to J.G.W.), and Generalitat de Catalunya (research group 2009 SGR 925, XRQTC, ICREA Academia prize for excellence in research to C.A.) is gratefully acknowledged.

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