CuZn superoxide dismutase geometry optimization, energetics, and redox potential calculations by density functional and electrostatic methods

The structures, energetics, and orbital- and charge-dependent properties of copper zinc superoxide dismutase (CuZnSOD) have been studied using density functional and electrostatic methods. The CuZnSOD was represented with a model consisting of copper and zinc sites connected by a bridging histidine ligand. In addition to the bridge, three histidine ligands and one water molecule were bonded to the Cu ion in the copper site as first-shell ligands. Two histidine ligands and an aspartate were coordinated to the zinc ion in the zinc site. Full optimization of the model was performed using different functionals, both local and nonlocal. Geometrical parameters calculated with the nonlocal functionals agree well with the experimental X-ray data. In our calculated results, the His61 N epsilon-Cu bond in the active site breaks during the reduction and protonation, consistent with a number of X-ray structures and with EXAFS and NMR evidence. The reduction potential and pK(a) of the coupled electron/proton reaction catalyzed by CuZnSOD were determined using different models for the extended environment-from an electrostatic representation of continuum solvent, to the full protein/solvent environment using a Poisson-Boltzmann method. The predicted redox potential and pK(a) values determined using the model with the full protein/solvent environment are in excellent agreement with experiment. Inclusion of the full protein environment is essential for an accurate description of the redox process. Although the zinc ion does not play a direct redox role in the dismutation, its electronic contribution is very important for the catalytic mechanism.