A self-consistent reaction field model of solvation using distributed multipoles. I. Energy and energy derivatives.

The self-consistent reaction field model developed previously by the authors in the case of single center multipole expansion of the electronic structure of the solute has been extended to the case of a distributed multipole expansion. Three different expansions have been tested and two of them have proved to be rapidly convergent. The performances of the code are illustrated by the density functional theory treatment of few test systems: guanine, cytosine, and cytosine hydrated with one and three water molecules. A robust fast computer code has been tested to get the electronic structure, the electrostatic contribution to the solute-solvent free energy of interaction, and the optimized molecular geometry in solution.

Density functional study of the mechanism of a tyrosine phosphatase: I. Intermediate formation.

The first step in the catalytic mechanism of a protein tyrosine phosphatase, the transfer of a phosphate group from the phosphotyrosine substrate to a cysteine side chain of the protein to form a phosphoenzyme intermediate, has been studied by combining density functional calculations of an active-site cluster with continuum electrostatic descriptions of the solvent and the remainder of the protein. This approach provides the high level of quantum chemical methodology needed to adequately model phosphotransfer reactions with a reasonable description of the environment around the active site. Energy barriers and geometries along a reaction pathway are calculated. In the literature, mechanisms assuming both a monoanionic and a dianionic substrate have been proposed; this disagreement is addressed by performing calculations for both possibilities. For the dianionic substrate, a dissociative reaction pathway with early proton transfer to the leaving group and a 9 kcal/mol energy barrier is predicted (the experimental estimate is ca. 14 kcal/mol), while for the monoanionic substrate, an associative pathway with late proton transfer and a 22 kcal/mol energy barrier is predicted. These results, together with a review of experimental evidence, support the dianionic-substrate/dissociative-pathway alternative. The relationship between a dianionic or monoanionic substrate and a dissociative or associative pathway, respectively, can be understood in terms of classical organic chemical reaction pathways.

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 Nepsilon-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.