Conformational study in water by NMR and molecular modeling of alpha-methyl-alpha-amino acid: Differential conformational properties of alpha-cyclic and alpha-methylglutamic acid

The 2-methylglutamic acid (2M) analogue was generally inactive in electrophysiological experiments and had generally worse functional activity. The low functional activity obtained with 2M would not be determined by only alpha substitution or C methylation, since the extensive biological studies of alpha,alpha'-dialkyl cyclic analogues of glutamic acid containing a cyclohexane and a cyclopentane ring or beta- or gamma-methylated glutamic acid analogues with linear flexible systems have indicated interesting properties. A conformational analysis by H-1 and C-13 NMR spectroscopy and molecular modeling of 2M was undertaken in aqueous solution to identify the preferred solution conformations and to understand whether its different biological activities would be due to structural differences. The preferred conformation of the 2M molecule is the sterically favored one Ca, corresponding to a large ''W'' between the methyl and the carboxylate groups mixed with Aa showing a large zig-zag alkylamine chain ending in a carboxylate group, or Ba, corresponding to a large ''W'' between the amino and the carboxylate groups.