We used quantum-chemical methods to study mechanisms of monoamine oxidase (MAO) inhibition by two acetylenic inhibitors, rasagiline and selegiline. Our DFT calculations on cluster models and under solvent reaction field of moderate polarity, found that a polar anionic mechanism, involving deprotonation of the inhibitor molecule at the terminal acetylene carbon atom, is the most plausible. The calculated free energies of activation are in very good agreement with experimentally determined values. The results lead to better understanding of the nature of MAO inhibition and have possible application in the design of new antiparkinsonians as improved MAO B inhibitors.
COBISS.SI-ID: 4788506
Hydration of histamine was examined by infrared spectroscopy and Car-Parrinello molecular dynamics simulation. Histamine is a neurotransmitter and inflammation mediator, which at physiological pH conditions is present mainly in monocationic form. Our focus was on the part of vibrational spectra that corresponds to histamine N-H stretching, since these degrees of freedom are essential for its interactions with either water molecules or transportersand receptors. Assignment of the experimental spectra revealed a broad feature between 3350 and 2300 cm-1, being centered at 2950 cm-1, which includes a mixed contribution from the ring N-H and the aminoethyl N-H stretching vibrations. Computational analysis was performed in two ways: first, by making Fourier transformation on the autocorrelation function of allfour N-H bond distances recorded during CPMD run, and second, and most importantly, by incorporating quantum effects through applying an a posterioriquantization of all N-H stretching motions utilizing our snapshot analysis of the fluctuating proton potential. The one-dimensional vibrational Schro dinger equation was solved numerically for each snapshot, and the N-H stretching envelopes were calculated as a superposition of the 0)1 transitions. The agreement with the experiment was much better in the case of the second approach. Our calculations clearly demonstrated that the ring aminogroup absorbs at higher frequencies than the remaining three amino N-H protons of the protonated aminoethyl group, implying that the chemical bondingin the former group is stronger than in the three amino N-H bonds, thusforming weaker hydrogen bonding with the surrounding solvent molecules. Inthis way the results of the simulation complemented the experimental spectrum that cannot distinguish between the two sets of protons. The effects of deuteration were also considered. The resulting N-D absorption is narrower and red-shifted. The presented methodology is of general applicability to strongly correlated systems, and it is particularly tuned to provide computational support to vibrational spectroscopy. Perspectives are given for its future applications in computational studies of tunneling in enzyme reactive centers and for receptor activation.
COBISS.SI-ID: 4658202
Hydrogen bonding and proton transfer in the solid state are studied on the crystals of isostructural anhydrous potassium and rubidium complex chloranilates by variable-temperature single crystal X-ray diffraction, solid state 1H NMR and IR spectroscopies, and periodic DFT calculations of equilibrium geometries, proton potentials, and NMR chemical shifts. Their crystal structures reveal neutral molecules of chloranilic acid and its dianions connected into a chain by O-H O hydrogen bond. A strong hydrogen bond with a large-amplitude movement of the proton with NMR shift of 13-17 ppmand a broad continuum in IR spectra between 1000 and 500 cm-1 were observed. Periodic DFT calculations suggest that proton transfer is energetically more favorable if it occurs within a single pair of chloranilatedianion and chloranilic acid molecule but not continuously along the chains of long periodicity. The calculated chemical shifts confirm the assumption that the weak resonance signals observed at lower magnetic fields pertain to the case when the proton migrates to the acceptor side of the hydrogen bond. The detected situation can be described by a partial proton transfer.
COBISS.SI-ID: 4646938