Biological control of S-nitrosothiol reactivity: potential role of sigma-hole interactions.

S-Nitrosothiols (RSNOs) are ubiquitous biomolecules whose chemistry is tightly controlled in vivo, although the specific molecular mechanisms behind this biological control remain unknown. In this work, we demonstrate, using high-level ab initio and DFT calculations, the ability of RSNOs to participate in intermolecular interactions with electron pair donors/Lewis bases (LBs) via a σ-hole, a region of positive electrostatic potential on the molecular surface at the extension of the N-S bond. Importantly, σ-hole binding is able to modulate the properties of RSNOs by changing the balance between two chemically opposite (antagonistic) resonance components, R-S[double bond, length as m-dash]N-O (D) and R-S/NO (I), which are, in addition to the main resonance structure R-S-N[double bond, length as m-dash]O, necessary to describe the unusual electronic structure of RSNOs. σ-Hole binding at the sulfur atom of RSNO promotes the resonance structure D and reduces the resonance structure I, thereby stabilizing the weak N-S bond and making the sulfur atom more electrophilic. On the other hand, increasing the D-character of RSNO by other means (e.g. via N- or O-coordination of a Lewis acid) in turn enhances the σ-hole bonding. Our calculations suggest that in the protein environment a combination of σ-hole bonding of a negatively charged amino acid sidechain at the sulfur atom and N- or O-coordination of a positively charged amino acid sidechain is expected to have a profound effect on the RSNO electronic structure and reactivity.