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J Phys Chem B. 2015 Apr 30;119(17):5386-91. doi: 10.1021/acs.jpcb.5b01051. Epub 2015 Apr 21.

Redox potentials of protein disulfide bonds from free-energy calculations.

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†Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany.


Thiol/disulfide exchange in proteins is a vital process in all organisms. To ensure specificity, the involved thermodynamics and kinetics are believed to be tailored by the structure and dynamics of the protein hosting the thiol/disulfide pair. We here aim at predicting the thermodynamics of thiol/disulfide pairs in proteins. We devise a free-energy calculation scheme, which makes use of the Crooks Gaussian intersection method to estimate the redox potential of thiol/disulfide pairs in 12 proteins belonging to the thioredoxin superfamily, namely, thioredoxins, glutaredoxins, and thiol-disulfide oxidoreductases in disulfide bond formation systems. We obtained a satisfying correlation of computed with experimental redox potentials (varying by 160 mV), with a residual error of ∼40 mV (8 kJ/mol), which drastically reduces when considering a less diverse set of only thioredoxins. Our simple and transferrable approach provides a route toward estimating redox potentials of any disulfide-containing protein given that its (reduced or oxidized) structure is known and thereby represents a step toward a rational design of redox proteins.

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