On the possible biological relevance of HSNO isomers: a computational investigation

Abstract

Thionitrous acid (HSNO), the smallest S-nitrosothiol, has been identified as a potential biologically active molecule that connects the biochemistries of two important gasotransmitters, nitric oxide (NO) and hydrogen sulfide (H₂S). Here, we computationally explore possible isomerization reactions of HSNO that may occur under physiological conditions using high-level coupled-cluster as well as density functional theory and composite CBS-QB3 methodology calculations. Gas-phase calculations show that the formation of the tautomeric form HONS and the Y-isomer SN(H)O is thermodynamically feasible, as they are energetically close, within ∼6 kcal mol⁻¹, to HSNO, while the recently proposed three-membered ring isomer is not thermodynamically or kinetically accessible. The gas-phase intramolecular proton-transfer reactions required for HSNO isomerization into HONS and SN(H)O are predicted to have prohibitively high reaction barriers, 30–50 kcal mol⁻¹. However, the polar aqueous environment and water-assisted proton shuttle should decrease these barriers to ∼9 kcal mol⁻¹, which makes these two isomers kinetically accessible under physiological conditions. Our calculations also support the possibility of an aqueous reaction between the Y-isomer SN(H)O and H₂S leading to biologically active nitroxyl HNO. These results suggest that the formation of HSNO in biological milieu can lead to various derivative species with their own, possibly biologically relevant, activity.