TY - JOUR

T1 - Metallothionein Zn(2+)- and Cu(2+)-clusters from first-principles calculations.

A1 - Greisen,Per Junior

A1 - Jespersen,Jakob Berg

A1 - Kepp,Kasper Planeta

AU - Greisen,Per Junior

AU - Jespersen,Jakob Berg

AU - Kepp,Kasper Planeta

PB - Royal Society of Chemistry

PY - 2012

Y1 - 2012

N2 - 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 ∼0.02-0.03 Å 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 Å and 2.30-2.34 Å, whereas bridging M-S bonds are 0.05-0.11 Å 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 β-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.

AB - 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 ∼0.02-0.03 Å 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 Å and 2.30-2.34 Å, whereas bridging M-S bonds are 0.05-0.11 Å 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 β-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.

U2 - 10.1039/c1dt11785h

DO - 10.1039/c1dt11785h

JO - Dalton Transactions (Print Edition)

JF - Dalton Transactions (Print Edition)

SN - 1477-9226

IS - 8

VL - 41

SP - 2247

EP - 2256

ER -