Enabling molecular simulations of hydrogen persulfide in chemistry and biology


Sulfur is the thirteenth most abundant element in earth’s crust. The presence of sulfur at concentration > 0.5%, results in sour crude oil that is costly to refine and hence undesirable. Sulfur exists in biological systems as part of the amino acids cysteine and methionine. Cysteine is a semi-essential proteinogenic amino acid. It is comprised partly of a thiol side chain that often participates in enzymatic reactions, as a nucleophile. Research has revealed that the thiol is susceptible to oxidation, which yields the disulfide derivative cystine that serves an important structural role in many proteins. In fact, oxidative post-translational modifications upon reaction with oxygen and nitrogen species have long been known as regulators of protein structure and function and as important redox signaling mechanisms. S-Sulfhydration (to form the Cysteine-SSH persufilde) has recently been identified as an oxidative post-translational modification of cysteine that regulates oxidative stress and redox signaling. Hydrogen persulfide (H2S2), also known as hydrogen disulfide, dihydrogen disulfide, sulfane and disulfane, is the simplest molecule with an S–S bond, ubiquitous in protein structures. Experimentally, hydrogen persulfides can be obtained by fractional distillation under vacuum of a mixture of a sodium polysulfide solution with concentrated hydrochloric acid. Unfortunately, despite their paramount biological importance, little is known about the chemistry and chemical biology of persulfides.

A careful review of existing literature shows that the H2S2 molecule has been studied extensively both experimentally and theoretically, but a great deal of the previous studies has mostly focused on gaseous H2S2. So, while the structure, torsional potential, and vibrational frequencies of H2S2 are accurately established, properties of the liquid state are scarce in the literature. Worse off, properties of aqueous H2S2 and its interaction with amino acids have not been investigated to date. To address this, researchers from the Centre for Research in Molecular Modeling (CERMM) and the Department of Chemistry and Biochemistry at Concordia University in Quebec, Canada, Dr. Esam Orabi (postdoctoral fellow) and Professor Gilles Peslherbe, CERMM Director, carried out a detailed computational investigation of (H2S2)n, (H2S2)m.H2O, and (H2O)m.H2S2 clusters (n = 1–3, m =1,2), as well as of H2S2 complexes with nineteen compounds that model the side chains of the twenty naturally occurring amino acids. Their work has recently been published in the research journal Physical Chemistry Chemical Physics.

The authors focused on developing a simple non-polarizable model for H2S2 which was used to investigate properties of pure and aqueous H2S2 solutions, and was calibrated for H2S2–protein interactions, hence affording a reliable tool for investigating H2S2 in both chemical and biological contexts. Generally, their computational methodology commenced with the implementation of ab initio quantum chemical calculations, followed by molecular mechanics calculations.

They reported that the high polarizability of S warrants the use of large, very diffuse, basis sets for proper description of H2S2 and its complexes by quantum chemical calculations. Also, the computational investigation revealed that H2S2 possess 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 was preserved in all neutral and cationic complexes while a cis geometry prevailed in some anionic complexes. Additionally, H2S2 was found to be a better H-bond donor and a poorer acceptor than H2S, and that in complexes with water, alcohols and amines, H2S2 was a better H-bond donor.

In summary, the study reported on 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. A simple additive model was then optimized for H2S2 and used together with the TIP3P model and the CHARMM36 all-atom force field to investigate the structure and thermodynamic properties of liquid H2S2 and the solubility of H2S2 in water, and to model H2S2–protein interactions. In an interview with Advances in Engineering, Professor Gilles Peslherbe the lead author emphasized that their study did not only provide a thorough description of the structure and energetics of H2S2 and its various complexes, but also yielded a general and reliable force field for investigating H2S2 in chemistry and biology through molecular modeling and computer simulations.


Esam A. Orabi, Gilles H. Peslherbe. Computational insight into hydrogen persulfide and a new additive model for chemical and biological simulations. Physical Chemistry Chemical Physics, 2019, volume 21, page 15988.

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