Conformational analysis by NMR spectroscopy, molecular dynamics simulation in water and X-ray crystallography of glutamic acid analogues: isomers of 1-aminocyclopentane-1,3-dicarboxylic acid

Abstract

The conformational analysis of two isomeric glutamic acid analogues containing a cyclopentane ring, substituted in position 1 by an amino and a carboxyl group, and in position 3 by a second carboxyl group has been carried out in an aqueous environment, by ¹H and ¹³C NMR spectroscopy, and molecular dynamics (MD). The X-ray structure of the trans-isomer is included in this study. These cis and trans analogues may display envelope E or ‘twist’T conformations in aqueous solution. The definition of cis and trans is relative to the arrangement of the carboxyl function. This study shows four conformational families I–IV with characteristic distances between the potentially active functional groups, α-NH₃⁺–γ-CO₂^–-y and α-CO₂^––γ-CO₂^–. At physiological pH, the amino group in the cis-isomer 1 is found to be axial (²E or E₃ conformers), both carboxyl groups being in equatorial positions to reduce the steric energy (type II). In the trans-isomer 2, a 1,3-electrostatic attraction stabilizes the E₁ or ⁵E conformers with the α-NH₃⁺ and γ-CO₂^– in an axial or isoclinal position (type I). Conversely, at isoelectrie pH when the 3-carboxylate group is protonated, each isomer is represented by new privileged conformations. The cis-isomer 1 exhibits a E₅ conformation in which the 1-carboxylate group, α-CO₂^–, is axial and stabilized by an electrostatic interaction with the 3-carboxyl group, γ-CO₂H, less equatorial (type IV). For the trans-isomer 2, the steric parameters favour the E₂ or ³E conformations, in which the two carboxy groups are shown to be equatorial or isoclinal and the amino group axial (type III).

The data obtained may be considered as important elements in the recognition features of these glutamic acid analogues in biological systems (NMDA or ACPD receptors of the central nervous system, glutamine synthetase, D-glutamate-adding enzyme, etc.).