Prediction of pKa and redox properties in the thioredoxin superfamily

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 pKas and redox potentials in the thioredoxin superfamily is introduced. The results are compared with experimental pKa 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 ΔpKas. The motif itself and the overall framework regulate pKa variation. The reported method includes generation of multiple side-chain rotamers for the CxxC motif and is an effective predictive tool for functional pKa variation across the superfamily. Redox potential follows the trend in cysteine pKa 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.