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

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 <i>N</i>-acetylated derivative (Ac–His–OMe) in the isolated phase and in solution. To this end, we employed spectroscopic techniques (¹H 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 ³<i>J</i>_HH 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 Analysis and Intramolecular Interactions of l‑Proline Methyl Ester and Its <i>N</i>‑Acetylated Derivative through Spectroscopic and Theoretical Studies

This work reports a detailed study regarding the conformational preferences of l-proline methyl ester (ProOMe) and its <i>N</i>-acetylated derivative (AcProOMe) to elucidate the effects that rule their behaviors, through nuclear magnetic resonance (NMR) and infrared (IR) spectroscopies combined with theoretical calculations. These compounds do not present a zwitterionic form in solution, simulating properly amino acid residues in biological media, in a way closer than amino acids in the gas phase. Experimental ³<i>J</i>_HH coupling constants and infrared data showed excellent agreement with theoretical calculations, indicating no variations in conformer populations on changing solvents. Natural bond orbital (NBO) results showed that hyperconjugative interactions are responsible for the higher stability of the most populated conformer of ProOMe, whereas for AcProOMe both hyperconjugative and steric effects rule its conformational equilibrium