The catalytic cycles of a new generation of the GPx mimic, selenosubtilisin and tellurosubtilisin, were illuminated via the density functional theory and solvent-assisted proton exchange (SAPE) procedure to show the indirect proton exchange through a hydrogen-bonded transfer network. The reactivity of selenosubtilisin and tellurosubtilisin toward methanethiol as a reduction step and hydrogen peroxide as an oxidation step were investigated. The results show that all steps of the proposed catalytic cycles are spontaneous and kinetically favorable. From the kinetics viewpoint, the oxidation of selenic acid (ΔG≠ = 23.86 kcal mol−1) and tellurenic acid (ΔG≠=20.66 kcal mol−1) are considered as the rate-determining steps. The comparison of the barriers for oxidation/reduction of the chalcogens shows a decay from the selenosubtilisin to tellurosubtilisin. On the basis of the turnover frequency calculations, the catalytic cycle of tellurosubtilisin is faster than that of selenosubtilisin, because of the lower span energy. To confirm the nature of bond cleavage/formation, during the catalytic reactions, topological analyses were applied by using the quantum theory of atoms in molecules procedure. The high values of the electron localization function (ELF) and localized orbital locator (LOL) at the transition state regions, calculated by the multi-WFN program, confirm the critical bond formation.

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