Comparing thiol and selenol reactivity towards peroxynitrite by computer simulation

Abstract

Peroxynitrite is a very reactive species implicated in a variety of pathophysiological cellular processes. Partic-ularly, peroxynitrite-mediated oxidation of cellular thiol-containing compounds such as cysteine residues is a keyprocess which has been extensively studied. Cysteine plays roles in many redox biochemistry pathways. Incontrast, selenocysteine, the 21st amino acid, is only present in 25 human proteins. Investigating the molecularbasis of selenocysteine’s reactivity may provide insights into its unique role in these selenocysteine-containingproteins. The two-electron oxidation of thiols or selenols by peroxynitrite is a process that is carried out bythe thiolate/selenate forms and peroxynitrous acid.In this work, we shed light on the molecular basis of the differential reactivity of both species towards per-oxynitrite by means of state-of-the-art computer simulations. We performed electronic structure calculations ofthe reaction in the methanethiolate and methaneselenolate model systems with peroxynitrous acid at differentlevels of theory using an implicit solvent scheme. In addition, we employed a multi-scale quantum mechanics/molecular mechanics approach for obtaining free energy profiles of these chemical reactions in aqueous solution,which enabled the comparison between the simulations and the available experimental data. Our results suggestthat the larger reactivity observed in the selenocysteine case at physiological pH is mainly due to the lower pKa,which affords a larger fraction of the reactive anionic species in these conditions, and in a second place to aslightly enhanced intrinsic reactivity of the selenate form due to its larger nucleophilicity.