Computational Modeling of the Catalytic Cycle of Glutathione Peroxidase Nanomimic

To elucidate the role of a derivative of ebselen as a mimic of the antioxidant selenoenzyme glutathione peroxidase, density functional theory and solvent-assisted proton exchange (SAPE) were applied to model the reaction mechanism in a catalytic cycle. This mimic plays the role of glutathione peroxidase through a four-step catalytic cycle. The first step is described as the oxidation of 1 in the presence of hydrogen peroxide, while selenoxide is reduced by methanthiol at the second step. In the third step of the reaction, the reduction of selenenylsulfide occurs by methanthiol, and the selenenic acid is dehydrated at the final step. Based on the kinetic parameters, step 4 is the rate-determining step (RDS) of the reaction. The bond strength of the atoms involved in the RDS is discussed with the quantum theory of atoms in molecules (QTAIM). Low value of electron density, ρ­(r), and positive Laplacian values are the evidence for the covalent nature of the hydrogen bonds rupture (O₃₀–H₃₁, O₃₃–H₃₄). A change in the sign of the Laplacian, L(r), from the positive value in the reactant to a negative character at the transition state indicates the depletion of the charge density, confirming the N₅–H₁₀ and O₁₁–Se₁ bond breaking. The analysis of electron location function (ELF) and localized orbital locator (LOL) of the Se₁–N₅ and Se₁–O₁₁ bonds have been done by multi-WFN program. High values of ELF and LOL at the transition state regions between the Se, N, and O atoms display the bond formation. Finally, the main donor–acceptor interaction energies were analyzed using the natural bond orbital analysis for investigation of their stabilization effects on the critical bonds at the RDS.