Computational insight into hydrogen persulfide and a new additive model for chemical and biological simulations

Abstract

S-Sulfhydration of cysteine to the Cys-SSH persulfide is an oxidative post-translational modification that plays an important regulatory role in many physiological systems. Though hydrogen persulfide (H₂S₂) has recently been established as a signaling and cellular sulfhydration reagent, the chemistry and chemical biology of persulfides remain poorly explored. We first report an extensive high-level ab initio quantum chemical investigation of (H₂S₂)_n, (H₂S₂)_m·H₂O, and (H₂O)_m·H₂S₂ clusters (n = 1–3 and m = 1, 2) and of H₂S₂ complexes with 19 compounds that model the side chains of naturally-occurring amino acids. The high polarizability of S necessitates the use of large, very diffuse, basis sets for proper description of H₂S₂ and its complexes. H₂S₂ possesses a skewed equilibrium geometry, with nonpolar trans and more polar cis conformers 6 and 8 kcal mol⁻¹ higher in energy, respectively; the skewed conformation is preserved in all neutral and cationic complexes while a cis geometry prevails in some anionic complexes. H₂S₂ is found to be a better H-bond donor and a poorer acceptor than H₂S, and that in complexes with H₂O, alcohols and amines, H₂S₂ is a better H-bond donor. Radical delocalization on both S atoms stabilizes the perthiyl (HSS˙) over the thiyl (HS˙) radical and results in a ∼20 kcal mol⁻¹ lower S–H homolytic bond dissociation in H₂S₂, making it a potential antioxidant. A simple additive model is optimized for H₂S₂ and used together with the TIP3P model and the CHARMM36 all-atom force field (FF) to investigate the structure and thermodynamic properties of liquid H₂S₂ and the solubility of H₂S₂ in water, and to model H₂S₂–protein interactions (for which new FF parameters are further developed). Very weak H-bonding characterizes liquid H₂S₂ and it is found immiscible in liquid water with a trend in H-bonding strengths between H₂S₂ and H₂O in the order O–H⋯O ≫ S–H⋯O > O–H⋯S. This work does not only provide a thorough description of the structure and energetics of H₂S₂ and its various complexes, but also yields a reliable FF for investigating H₂S₂ in chemistry and biology.