Conformational study of L-methionine and L-cysteine derivatives through quantum chemical calculations and ³J_HH coupling constant analyses

Abstract

The understanding of the conformational behavior of amino acids and their derivatives is a challenging task. Here, the conformational analysis of esterified and N-acetylated derivatives of L-methionine and L-cysteine using a combination of 1H NMR and electronic structure calculations is reported. The geometries and energies of the most stable conformers in isolated phase and taking into account the implicit solvent effects, according to the integral equation formalism polarizable continuum model (IEF−PCM), were obtained at the ωB97X-D/aug-cc-pVTZ level. The conformational preferences of the compounds in solution were also determined from experimental and theoretical 3 J HH coupling constants analysis in different aprotic solvents. The results showed that the conformational stability of the esterified derivatives is not very sensitive to solvent effects, whereas the conformational equilibrium of the N-acetylated derivatives changes in the presence of solvent. According to the natural bond orbital (NBO), quantum theory of atoms in molecules (QTAIM) and noncovalent interactions (NCI) methodologies, the conformational preferences for the compounds are not dictated by intramolecular hydrogen bonding, but by a joint contribution of hyperconjugative and steric effects.

Revealing the Conformational Preferences of Proteinogenic Glutamic Acid Derivatives in Solution by 1H NMR Spectroscopy and Theoretical Calculations

“…Although theoretical calculations indicate the conformational equilibrium of GluOMe is not very sensitive to solvent effects, the variations observed in the signal of H a upon solvent change show that the conformational equilibrium of GluOMe changes when the solvent polarity increases from CDCl 3 to DMSO. As the theoretical calculations are consistent with the results obtained in CDCl 3 , CD 2 Cl 2 , and CD 3 CN and the level of theory (ωB97X-D/aug-cc-pVTZ) used in the present study has presented coherent results for similar studied systems, − the differences observed between theoretical and experimental data in DMSO can possibly be attributed to the use of an implicit solvent model in the study. It is likely that the implicit solvent model does not consider some specific interaction that occurs in GluOMe when the solvent is DMSO- d 6 .…”

“…The AcGluOMe derivative differs from GluOMe due to the presence of an amide group instead of the amine group. Most of the conformers of AcGluOMe (Figure S20) present the amide linkage anti to the C­(O)­OMe group of the backbone, which follows the same trend observed for other N -acetylated amino acid derivatives previously studied in the literature. − Contrary to what was observed for the conformers of GluOMe, no conformers a are observed for AcGluOMe and thus, the conformational equilibrium of this compound is governed by only conformers that present arrangements b and c .…”

“…Furthermore, glutamic acid also has a relatively long side chain, which gives rise to many low energy conformers, making the theoretical calculations challenging. An alternative, which has been shown to be useful in the investigation of amino acid derivatives in solution, is the study of amino acids esterified and N -acetylated derivatives. − These derivatives are soluble in most of organic solvents and thus, their conformational equilibrium can be studied by 1 H NMR spectroscopy. Moreover, some studies have shown that the identification of N -acetyl amino acid compounds in body fluids can be associated with inborn metabolism errors and neurological diseases. − In this sense, knowing the structures adopted by these derivatives, as well as the effects ruling their conformational preferences is relevant.…”