Reactivity of polynuclear zinc-thiolate sites

The proton affinities of a series of mono- and polynuclear zinc-thiolate compounds, mimicking zing finger protein and metallothioneins (MTs) sites, have been investigated by density functional theory calculations. This allows to evaluate the intrinsic nucleophilicity of synthetic and natural zinc-bound thiolates and to compare their relative reactivities. The site specificity of the experimental thiolate alkylation for the Zn₄Cys₁₁ clusters in MTs is well reproduced, as well as the relative reactivities of ZnHis₂Cys₂, ZnHisCys₃, and ZnCys₄ zinc finger sites. Our results also show that terminal thiolates, bound to only one Lewis acid, are more reactive than bridging thiolates. Synthetic inorganic clusters and the Zn₄Cys₉His₂ cluster found in a cyanobacterial MT are less reactive than Zn₄Cys₁₁ and Zn₃Cys₉ clusters in MTs. These results allow discussing the influence of the protein backbone and residues on the reactivity of these natural clusters.