Oxidation reactivity of zinc-cysteine clusters in metallothionein
Résumé
Evaluating the reactivity of the metal-thiolate clusters in metallothionein (MT) is a key step in understanding the biological functions of this protein. The effects of the metal clustering and protein environment on the thiolate reactivity with the hydrogen peroxide (H2O2) were investigated by performing quantum theory calculations with chemical accuracy at two levels of complexity. At the first level, the reactivity with H2O2 of a model system ([(Zn)3(MeS)9]3-, MeS for methanethiolate) of the b domain cluster of MT was evaluated using the density functional theory (DFT) with the mPW1PW91 functional. At the second level of complexity, the protein environment was included in the reactant system and the calculations were performed with the hybrid ONIOM method combining the DFT- mPW1PW91 and the semi-empiric PM6 levels of theory. In these conditions, the energy barrier for the oxidation of the most reactive terminal thiolate was 16.5 kcal mol-1. This is 2 kcal mol-1 lower than that calculated for the terminal thiolate in the model system [(Zn)3(MeS)9]3- but about 2 kcal mol-1 higher than that obtained for the free thiolate. Substitution of a zinc atom by a cadmium atom induced a supplementary increase in the energy barrier of about 2 kcal mol-1. It is concluded that the thiolate oxidation by H2O2 provides an efficient way for the metal release from MT. On the other hand, the present results suggest that the antioxidant role of MT in the living cell cannot be as important as that of glutathione (that carries a free thiol).