Metallothionein Zn2+- and Cu2+-clusters from first-principles calculations

被引:8
作者
Greisen, Per [2 ]
Jespersen, Jakob B. [1 ]
Kepp, Kasper P. [1 ]
机构
[1] Tech Univ Denmark, DTU Chem, DK-2800 Lyngby, Denmark
[2] Tech Univ Denmark, DTU Phys, DK-2800 Lyngby, Denmark
关键词
MOLECULAR-DYNAMICS SIMULATION; NUCLEAR-MAGNETIC-RESONANCE; GROWTH-INHIBITORY FACTOR; THIOLATE CLUSTERS; ZINC TRANSFER; CRYSTAL-STRUCTURE; 3-DIMENSIONAL STRUCTURE; METAL-BINDING; BETA-DOMAIN; DNA-BINDING;
D O I
10.1039/c1dt11785h
中图分类号
O61 [无机化学];
学科分类号
070301 ; 081704 ;
摘要
Detailed electronic structures of Zn(II) and Cu(II) clusters from metallothioneins (MT) have been obtained using density functional theory (DFT), in order to investigate how oxidative stress-caused Cu(II) intermediates affect Zn-binding to MT and cooperatively lead to Cu(I) MT. The inferred accuracy is similar to 0.02-0.03 angstrom for metal-thiolate bond lengths for the models that are the most realistic MT models so far studied by DFT. We find terminal Zn-S and Cu-S bond lengths of 2.35-2.38 angstrom and 2.30-2.34 angstrom, whereas bridging M-S bonds are 0.05-0.11 angstrom longer. This electronic effect is also reflected in changes in electron density on bridging sulfurs. Various imposed backbone constraints quantify the sensitivity of cluster electronic structure towards protein conformational changes. The large negative charge densities of the clusters are central to MT function, and the smaller beta-clusters are more prone to modification. Oxidative stress-associated Cu(II) binding weakens the Zn-S bonds and is thus likely to impair the Zn(II) transfer function of MTs, providing a mechanism for cooperative Cu(II) binding leading to loss of Zn(II) and dysfunctional Cu(I) MT clusters.
引用
收藏
页码:2247 / 2256
页数:10
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