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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-HO » S-HO > O-HS. 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.