Theoretical investigation of the mechanism of nitroxyl decomposition in aqueous solution

MAURO BRINGAS; JONATHAN SEMELAK; ARI ZEIDA; DARIO 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 biochemical reactions 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 calculations aswell as state of the art hybrid quantummechanics/molecular mechanics molecular dynamics simulations. We characterized the reaction mechanismand computed free energy profiles for the reaction steps using an umbrella sampling 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 conjugate basis as intermediate. Our calculations show preference for the anionic pathway under physiological conditions and allow us 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 the free energy barriers. We predict a strong pH-dependence of the overall kinetics of N2O formation, related with the fraction of reactive species available in solution. Finally, we suggest experimental procedures which could validate this mechanism.