The building blocks of metallothioneins: heterometallic Zn2+ and Cd2+clusters from first-principles calculations

Abstract

Electronic structures of Zn²⁺ and Cd²⁺ thiolate clusters found in metallothioneins (MT) have been obtained using density functional theory. We have found that the inherent asymmetry of cluster architectures gives rise to seven distinct metal sites. Whereas the non-strained bond lengths of such tetrathiolate complexes are found to be 2.60 Å and 2.39 Å for Cd–S and Zn–S, in the MT clusters four characteristic terminal and bridging bonds are observed with average lengths 2.55 Å (Cd–S^t); 2.35 Å (Zn–S^t); 2.62 Å (Cd–S^b); and 2.42 Å (Zn–S^b). For each stoichiometry of Zn²⁺ and Cd²⁺, all possible isomers have been characterized and ranked according to relative free energy and metal ion selectivity. The most stable distribution at low Cd²⁺ concentration is computed to be Zn₄ + CdZn₂, whereas at 2 : 1 Cd²⁺ : Zn²⁺ concentration, only heteroclusters are thermodynamically stable, explaining experimental data. The presence of two different clusters in MTs must and can be rationalized already in their intrinsic differences. The results indicate that the asymmetry allows for Zn²⁺ transfer to various molecular targets having different thresholds for Zn²⁺ binding, while maintaining detoxification sites.