Issue 8, 2015

The influence of zinc(ii) on thioredoxin/glutathione disulfide exchange: QM/MM studies to explore how zinc(ii) accelerates exchange in higher dielectric environments

Abstract

QM/MM studies were performed to explore the energetics of exchange reactions of glutathione disulfide (GSSG) and the active site of thioredoxin [Cys32–Gly33–Pro34–Cys35] with and without zinc(II), in vacuum and solvated models. The activation energy for exchange, in the absence of zinc, is 29.7 kcal mol−1 for the solvated model. This is 3.3 kcal mol−1 higher than the activation energy for exchange in the gas phase, due to ground state stabilization of the active site Cys-32 thiolate in a polar environment. In the presence of zinc, the activation energy for exchange is 4.9 kcal mol−1 lower than in the absence of zinc (solvated models). The decrease in activation energy is attributed to stabilization of the charge-separated transition state, which has a 4-centered, cyclic arrangement of Zn–S–S–S with an estimated dipole moment of 4.2 D. A difference of 4.9 kcal mol−1 in activation energy would translate to an increase in rate by a factor of about 4000 for zinc-assisted thiol-disulfide exchange. The calculations are consistent with previously reported experimental results, which indicate that metal-thiolate, disulfide exchange rates increase as a function of solvent dielectric. This trend is opposite to that observed for the influence of the dielectric environment on the rate of thiol-disulfide exchange in the absence of metal. The results suggest a dynamic role for zinc in thiol-disulfide exchange reactions, involving accessible cysteine sites on proteins, which may contribute to redox regulation and mechanistic pathways during oxidative stress.

Graphical abstract: The influence of zinc(ii) on thioredoxin/glutathione disulfide exchange: QM/MM studies to explore how zinc(ii) accelerates exchange in higher dielectric environments

Supplementary files

Article information

Article type
Paper
Submitted
09 mar 2015
Accepted
28 mai 2015
First published
28 mai 2015

Metallomics, 2015,7, 1265-1273

Author version available

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