Methylmercury is a highly toxic compound and human exposure is mainly related to consumption of polluted fish and seafood. The inactivation of thiol-based enzymes, promoted by the strong affinity binding of electrophilic mercuric ions to thiol and selenol groups of proteins, is likely an important factor explaining its toxicity. A key role is played by the chemistry and reactivity of the mercury-chalcogens bond, particularly HgS and HgSe, which is the focus of this computational work (level of theory: (COSMO)-ZORA-BLYP-D3(BJ)/TZ2P). We analyze nine ligand-exchange model reactions (the so-called Rabenstein's reactions) involving an entering ligand (methylchalcogenolate) and a substrate (methylchalcogenolatemethylmercury). Trends in reaction and activation energies are discussed and a change in mechanism is reported for all cases when going from gas phase to water, that is, from a single-well potential energy surface (PES) to a canonical SN 2-like mechanism. The reasons accounting for the biochemically challenging and desired displacement of methylmercury from a seleno/thiol protein can be found already in these model reactions, as can be seen from the similarities of the ligand exchange reactions in solution in thermodynamics and kinetics.
Keywords: DFT calculations; Rabenstein's reactions; activation strain analysis; benchmark; in silico toxicology; ligand substitution; methylmercury; reaction mechanism; selenium; selenoproteins.
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