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

Abstract

Electronic structures of Zn 2+ and Cd 2+ 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 2.60Å and 2.39Å for Cd-S and Zn-S, in the MT clusters four characteristic terminal and bridging bonds are observed with average lengths 2.55Å (Cd-S t ); 2.35Å (Zn-S t ); 2.62Å (Cd-S b ); and 2.42Å (Zn-S b ). For each stoichiometry of Zn 2+ and Cd 2+ , all possible isomers have been characterized and ranked according to relative free energy and metal ion selectivity. The most stable distribution at low Cd 2+ concentration is computed to be Zn 4 + CdZn 2 , whereas at 2 : 1 Cd 2+ : Zn 2+ 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 Zn 2+ transfer to various molecular targets having different thresholds for Zn 2+ binding, while maintaining detoxification sites.

Bioinorganic Chemistry of Alzheimer’s Disease

“…Related to AD, Cd(II) may interrupt tau processing, 780 and Cd(II) bound to MT 781,782 will disturb metal binding sites and could possibly increase the free Zn 2+ pool while impairing Zn(II) transfer to zinc proteins, 532 which could cause MT dysfunction contributing to zinc dyshomeostasis, 783 although this is currently unexplored. Alternatively, due to its zincmimetic properties, Cd(II) may bind directly to regulatory zinc sites affecting APP processing, causing amyloid imbalance by direct zinc substitution of regulatory Zn 2+ instead of affecting the size of free Zn 2+ pool as above.…”

“…532 In mammals, four main MT classes are distinguished, with MT-1 and MT-2 present in most tissue, whereas MT-3 and MT-4 appear mainly (but not exclusively) in specialized tissue such as the brain and skin. 533 Brain MT-1/MT-2 is mainly expressed in glia cells and mainly in the astrocytes 534 that maintain homeostasis in the CNS, the integrity of the BBB, and the metabolism of neurons, 464 express extracellular metalloproteases that degrade amyloids, 94 and accumulate toxic exogenous metals such as Pb (possibly in MTs).…”

“…Brain homeostasis is governed by astrocytes, zinc homeostasis is governed by MTs, particularly expressed by astrocytes, and astrocytes are central cells in AD pathogenesis. 429 Dysfunctional MTs would increase the free Zn 2+ pool and reduce the bound, transferable Zn(II) pool, 532 thus increasing free Zn 2+ between synapses in neuropils, 146−148 while global zinc levels are reduced or unchanged in the brain, 152,168 due to redistribution toward extracellular deposits. As a compensation, MT-1/ MT-2 is up-regulated by free Zn 2+ and by other stress factors 527,539,541,554 as observed in AD.…”

Theoretical Study of Spin Crossover in 30 Iron Complexes

“…the accuracy of geometries of charged metal clusters68 , and some of the iron complexes have +2 charges, i.e. geometry optimization in a screened environment is important.Dielectric constants were used corresponding to the solvent of the experimental thermochemical data for each complex: 80 for H2O, 20 for CH3COCH3, 37 for CH3NCHOCH3 (formamide), 38 for CD3CN or CH3CN, 28 for CH3CH2CN, 33 for CH3OH, and a composition-weighted average for H2O-CH3CN and CH3CN-CH3OH mixtures.…”

Coordination of Bi3+ to metal-free metallothionein: Spectroscopy and density functional calculation of structure, coordination, and electronic excitations

“…Rulíšek's group calculated the coordination structures and interaction energies of amino acid side chains with metal ions by DFT [24]. Especially, DFT calculations have been used in studies of metal ion coordination structure and spectrum of MT [25][26][27][28][29]. Soldatov and coworkers performed the DFT geometry optimization of active Cd 2+ center in Cd-MT [25].…”