Combined Utilization of ¹H NMR, IR, and Theoretical Calculations To Elucidate the Conformational Preferences of Some l-Histidine Derivatives

Abstract

The conformational preferences of amino acids and their derivatives have been the subject of many investigations, because protein folding pathways that determine three-dimensional geometries are primarily restricted by the conformational space of each amino acid residue. Here we systematically describe the conformational behavior of l-histidine methyl ester (His-OMe) and its N-acetylated derivative (Ac-His-OMe) in the isolated phase and in solution. To this end, we employed spectroscopic techniques (H NMR and IR), supported by quantum chemical calculations. Initially, the energetically favorable conformers, their energies, and structural properties obtained by density functional theory (DFT) and Møller-Plesset perturbation theory (MP2) calculations in the isolated phase and in solution via the implicit solvation model IEF-PCM were presented. Next, experimental J spin-spin coupling constants obtained in different aprotic nonpolar and polar solvents were compared with the theoretically predicted ones for each conformer at the IEF-PCM/ωB97X-D/EPR-III level. A joint analysis of these data allowed the elucidation of the conformational preferences of the compounds in solution. Infrared data were also employed as a complement to estimate the His-OMe conformer populations. Finally, the quantum theory of atoms in molecules (QTAIM), the noncovalent interactions (NCI), and the natural bond orbitals (NBO) analyses were used to determine the intramolecular interactions that govern the relative conformational stabilities.

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

“…Another alternative would be the use of some chemical agent to break the disulfide bond in 2 , but it could induce changes in the conformational isomerism. However, the level of theory (ωB97X-D/aug-cc-pVTZ) used in this work for the studied compounds has shown good results for other amino acid derivatives, when comparing theoretical with experimental data [22–24]. Although 2 could not be experimentally studied, the theoretical calculations carried out strongly suggest that the conformational equilibrium of 2 and the populations of its conformers are not very sensitive to solvent effect.…”

“…Since the ωB97X-D/aug-cc-pVTZ level presented one of the smallest mean absolute deviation from MP2/aug-cc-pVTZ single point calculations (Table S1, Supporting Information File 1), assumed as the reference level, and as the ωB97X-D DFT functional has been recognized to reliably treat noncovalent interactions as well as to present good proximity with spectroscopic results [22–24], it was used in all subsequent calculations. These calculations were only performed for the conformers of 2 due to their size compared to the geometries of the L-Met esterified derivative.…”

“…For a deeper understanding of amino acid properties, an interplay between theoretical and experimental methods is crucial. Consequently, high-level quantum chemical calculations, such as the Møller–Plesset (MP2) method and density functional theory (DFT) calculations, together with experimental techniques have been combined to achieve more accurate results [20–24]. …”

“…Some amino acid derivatives have been recently studied by our research group, including the derivatives of tryptophan [20], phenylalanine and tyrosine [21], aspartic acid [22], proline [23] and histidine [24]. These studies have provided significant results to understand the importance of the corresponding amino acids in processes in which they take part in the polypeptide chain.…”

Characterization of acetylated histidine b1-ion structure: A competition between oxazolone and side chain imidazole moiety

“…26 A research study systematically described the conformational behaviour of L-histidine methyl ester (His-OMe) and its N-acetylated derivative (Ac-His-OMe) in the isolated phase and in solution by employing spectroscopic techniques ( 1 H nuclear magnetic resonance [NMR] and infrared [IR]), supported by quantum chemical calculations. 27 These studies show that the b þ 1 -ion of histidine is formed with side chain imidazole ring. Hence, the side chain facilitates formation of b 1 -ion with m/z 138.…”