Ebselen (1), the quintessential mimic of the antioxidant selenoenzyme glutathione peroxidase (GPx), is a potential chemopreventative for various diseases associated with oxidative stress. Density-functional theory (DFT) and solvent-assisted proton exchange (SAPE) are used to model the complex mechanism for scavenging of reactive oxygen species by 1. SAPE is a microsolvation method designed to approximate the role of bulk solvent in chemical processes involving proton transfer. Consistent with experimental studies, SAPE studies predict the reaction of 1 with thiol (RSH) to form a selenenyl sulfide 2 to be preferred under most conditions, with an alternate pathway through a selenoxide 3 possible at high reactive oxygen species (ROS) concentrations ([ROS] ≫ [RSH]). The reduction of 2 to the selenol 4, known to be rate-determining in the protein, has a high SAPE activation barrier due to a strong Se···O interaction which reduces the electrophilicity of the sulfur center of the -SeS- bond of 2. Thiols, such as dithiols and peptide-based thiols, are expected to overcome this barrier through structural features that increase the probability of attack at this sulfur. Thus, in vivo, the GPx-like pathway is the most likely mechanism for 1 under most circumstances, except, perhaps, under extreme oxidative stress where initial oxidation to 3 could compete with formation of 2. Simple thiols, used in various in vitro studies, are predicted by SAPE modeling to proceed through oxidation of 2 to a seleninyl sulfide intermediate. Overall, SAPE modeling provides a realistic interpretation of the redox mechanism of 1 and holds promise for further exploration of complex aqueous-phase reaction mechanisms.

Ab initio and density-functional theory (DFT) modeling have proven to be important tools in the determination of the properties and reactivity of selenium with respect to biological activity. In this review, we address recent applications of quantum chemistry in three areas of interest to selenium chemistry: theoretical 77 Se chemical shifts, analysis of SeÁ Á ÁN,O interactions important to redox chemistry and mechanistic determinations for selenoenzymes and small selenium molecules. High-performance computing and DFT have allowed for large-scale calculations of both the enzyme active site and solution-phase reactivity. The latter development is important for understanding the complex mechanisms of small molecule GPx mimics. Application of solvent-assisted proton exchange to the redox scavenging mechanism of PhSeH by our research group is highlighted.

The oxidation of dimethylselenide, dimethyldiselenide, S-methylselenenyl-methylmercaptan, and truncated and full models of ebselen (N-phenyl-1,2-benzisoselenazol-3(2H)-one) by methyl hydrogen peroxide has been modeled using density functional theory (DFT) and solvent-assisted proton exchange (SAPE), a method of microsolvation that employs explicit solvent networks to facilitate proton transfer reactions. The calculated activation barriers for these systems were substantially lower in energy (DeltaG(double dagger) + DeltaG(solv) = 13 to 26 kcal/mol) than models that neglect the participation of solvent in proton exchange. The comparison of two- and three-water SAPE networks showed a reduction in the strain in the model system but without a substantial reduction in the activation barriers. Truncating the ebselen model to N-methylisoselenazol-3(2H)-one gave a larger activation barrier than ebselen or N-methyl-1,2-benzisoselenazol-3(2H)-one but provided an efficient means of determining an initial guess for larger transition-state models. The similar barriers obtained for ebselen and Me(2)Se(2) (DeltaG(double dagger) + DeltaG(solv) = 20.65 and 20.40 kcal/mol, respectively) were consistent with experimentally determined rate constants. The activation barrier for MeSeSMe (DeltaG(double dagger) + DeltaG(solv) = 21.25 kcal/mol) was similar to that of ebselen and Me(2)Se(2) despite its significantly lower experimental rate for oxidation of an ebselen selenenyl sulfide by hydrogen peroxide relative to ebselen and ebselen diselenide. The disparity is attributed to intramolecular Se-O interactions, which decrease the nucleophilicity of the selenium center of the selenenyl sulfide.

Models of the tungstoenzyme acetylene hydratase (AH), which catalyzes the addition of water to acetylene through a nonredox process, are examined using density-functional theory (DFT). The relative energy of acetylene adduct formation was calculated for several tungsten-and molydbenumoxo dithiocarbamates (dtc) and dithiolates (dtl). Stronger coordination of acetylene to tungsten and dtc complexes is consistent with experimental K eq values and attributed to the larger W 5d orbitals and the overall negative charge of the dithiolate complexes. The recently solved AH X-ray crystal structure suggests the presence of a water molecule bonded to the metal and the possibility that catalysis occurs via a non-organometallic intermediate. Models of the truncated active site are used to analyze this claim by determining the relative energies of acetylene versus water coordination. Complexation of acetylene is favored over water by 12 kcal/mol with the aquo complex formation endergonic by 7 kcal/mol (ΔG). These results suggest that water may be easily replaced by acetylene such that catalysis occurs via an organometallic η 2 -acetylene intermediate. The selectivity of the enzyme for tungsten is discussed in terms of these results.

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