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International audience; The proton affinities of a series of mono- and polynuclear zinc-thiolate compounds, mimicking zing finger protein and metallothioneins 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 metallothioneins 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 metallothionein are less reactive than Zn4Cys11 and Zn3Cys9 clusters in metallothioneins. These results allow discussing the influence of the protein backbone and residues on the reactivity of these natural clusters.

Density Functional Theory and post-Hartree Fock calculations reveal an unusual energy profile for Zn-S and Zn-N bond dissociation reactions in several [Zn(SR)(4)](2-) and [Zn(Im)(SR)(3)](-) complexes. The Zn-S bond dissociation in tetrathiolate dianions, which is highly exothermic in the gas phase, proceeds through a late transition state which can be rationalized on the basis of an avoided crossing resulting from Coulomb repulsion between the anionic fragments and ligand-to-metal charge-transfer in the [Zn(SR)(4)](2-) complexes. When solvation models for water, DMSO, or acetonitrile are included, some complexes become stable while others are metastable, so this constitutes the first theoretical model which is in full agreement with the experimental data for various [Zn(SR)(4)](2-), [Zn(SR)(3)](-), and [Zn(Im)(SR)(3)](-) complexes. The analysis given here indicates that the Zn(Cys)(4) and Zn(His)(Cys)(3) cores of numerous proteins are metastable with respect to Zn-S and Zn-N bond dissociation, respectively. This is consistent with the kinetic lability at the zinc-centers and illustrates that in nature, thermodynamic stability is imparted upon the zinc cores by the protein environment.

International audience; The nucleophilicity of biomimetic zinc-thiolate complexes against methyl iodide has been studied. The activation barrier has been computed with the B3LYP functional. The reactivity depends on the global charge, the nature of the ligand set and the presence of hydrogen bonds. This shows that the understanding of zinc site nucleophilicity cannot be achieved by the knowledge of the atom donor set for zinc only, as currently done in the literature. Moreover, we show that sulfur proton affinity and activation barrier are directly proportional, thus providing a good nucleophilicity index for zinc-bound thiolate.