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Prediction of pK_a and redox properties in the thioredoxin superfamily

Biomolecular Sciences Department, University of Manchester Institute of Science and Technology (UMIST), Manchester M60 1QD, UK

(RECEIVED April 8, 2004; FINAL REVISION June 21, 2004; ACCEPTED June 21, 2004)

Electrostatic interactions play important roles in diverse biological phenomena controlling the function of many proteins. Polar molecules can be studied with the FDPB method solving the Poisson-Boltzmann equation on a finite difference grid. A method for the prediction of pK_as and redox potentials in the thioredoxin superfamily is introduced. The results are compared with experimental pK_a data where available, and predictions are made for members lacking such data. Studying CxxC motif variation in the context of different background structures permits analysis of contributions to cysteine pK_as. The motif itself and the overall framework regulate pK_a variation. The reported method includes generation of multiple side-chain rotamers for the CxxC motif and is an effective predictive tool for functional pK_a variation across the superfamily. Redox potential follows the trend in cysteine pK_a variation, but some residual discrepancy indicates that a pH-independent factor plays a role in determining redox potentials for at least some members of the superfamily. A possible molecular basis for this feature is discussed.

Keywords: electrostatics calculations; thioredoxin superfamily; ionizable groups; redox potential

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.04804504.

Reprint requests to: Jim Warwicker, Biomolecular Sciences Department, University of Manchester Institute of Science and Technology, Sackville Street, Manchester M60 1QD, UK; e-mail: jim.warwicker{at}umist.ac.uk; fax: +44-161-236-0409.

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