Theoretical investigation of the mechanism of nitroxyl decomposition in aqueous solution

M. BRINGAS; J. SEMELAK; A. ZEIDA; D.A. ESTRIN

JOURNAL OF INORGANIC BIOCHEMISTRY

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2016

0162-0134

Nitroxyl (HNO) is a species that has been proposed recently to play different roles in nitrosative stress processes.HNO decomposition in aqueous solution leading to N2O is a fast reaction that competes with many biochemicalreactions in which HNO may be involved. Since molecular determinants of this reaction are still not fully understood,we present in this work an exhaustive analysis of the mechanism in terms of electronic-structure calculationsaswell as state of the art hybrid quantummechanics/molecular mechanicsmolecular dynamics simulations.Wecharacterized the reaction mechanismand computed free energy profiles for the reaction steps using an umbrellasampling procedure. We propose a first dimerization step followed by an acid-base equilibria. Afterwards,the product is formed from two main pathways involving cis-hyponitrous acid (cis-HONNOH) and its conjugatebasis as intermediate. Our calculations show preference for the anionic pathway under physiological conditionsand allowus to rationalize the results in terms of amolecular description of specific interactionswith the solvent.These interactions turn out to be determinant in the stabilization of transition states and, thereby,modifying thefree energy barriers. We predict a strong pH-dependence of the overall kinetics of N2O formation, related withthe fraction of reactive species available in solution. Finally, we suggest experimental procedures which couldvalidate this mechanism.