We developed program package for variational solving of the time-independent Schrödinger equation. The program is coded in FORTRAN-95 and is aimed to solve the vibrational SE on a generalized potential energy hypersurface (PES). We tested the package for three distinct chemical problems; namely, the umbrella inversion of ammonia, OH stretching motion of sodium hydrogen bissulfate, and hydrogen dynamics in soybean lipoxygenase-1 (SLO-1), yielding good agreement with the available experimental and previously published computational data. The program package is available from the authors on request.
Hydration of histamine was examined by infrared spectroscopy and Car-Parrinello molecular dynamics simulation. Vibrational spectra and our calculations clearly demonstrated that the ring amino group forms weaker hydrogen bonds with water molecules than the alkyl amino group. The results are important for histamine transporters and histamine receptor activation.
On the basis of quantum chemical calculations, we have proposed a new two-step hydride mechanism for the MAO-catalysed oxidative deamination of amines. In the rate-limiting first step, through its N5 atom, the flavin abstracts a hydride anion from the substrate \alpha-carbon atom and forms a strong covalent adduct with the thus created cation. This is followed by flavin N1 deprotonation of the substrate amino group, facilitated with two active-site water molecules, to produce fully reduced flavin, FADH2, and neutral imine. We have demonstrated that our mechanism is in agreement with available experimental data and provided evidence against both traditional polar nucleophilic and single-electron radical pathways. These results provide valuable information for mechanistic studies on other flavoenzymes and for the design of new antidepressants and antiparkinsonian drugs.
In order to investigate features essential for the modes of action of MAO, we have calculated pKa values of three relevant tyrosine residues in the MAO B active site, with and without dopamine bound as the substrate (as well as the pKa of the dopamine itself in the active site). The calculated pKa values for Tyr188, Tyr398, and Tyr435 in the complex are found to be shifted upward relative to aqueous solution, ruling out the likelihood that they are viable proton acceptors. The altered tyrosine pKa values could be rationalized as an interplay of two opposing effects: insertion of positively charged bulky dopamine that lowers tyrosine pKa values, and subsequent removal of water molecules from the active site that elevates tyrosine pKa values, in which the latter prevails. We demonstrated that the dopamine amino group is most likely to be present in the active site in its protonated form, although is it inexpensive in terms of free energy to be deprotonated. This study is relevant for design of novel and improved MAO B inhibitors.
We used quantum-chemical methods to study seven possible mechanisms of monoamine oxidase (MAO) inhibition by acetylenic inhibitors, considering neutral, cationic, anionic and radical mechanisms. We demonstrated that polar anionic mechanism, involving deprotonation of the inhibitor molecule at the terminal acetylene carbon atom, is the most plausible. Radical and and cationic mechanism are not plausible. Together with additional experimental and theoretical work, the results presented here could lead to better understanding of the nature of MAO inhibition and possible design of new antiparkinsonians as improved MAO B inhibitors.