DEVELOPMENT OF NEW METHODS FOR PROTEIN LIGAND DOCKING

ThepKa'softitratablegroupsinproteins,orrathertheshifts relative to the pKa's of single amino acids in solution, are indicators of the local electrostatic environment of the groups. A good understanding of the electrostatic interactions within the solvated protein is required not only for prediction of pKa shifts, but also to gain a better understanding of the pH effects on protein stability and pH dependent conformational changes in proteins. The two primary approaches to modeling protein electrostatic properties are (1) continuum, and (2) explicit solvent models. We have recently completed a study where the solvent dielectric response was evaluated in a system of two oppositely charged ions in solution using explicit solvent; both the Ewald summation and spherical truncation methods were used and compared. From this study, the Ewald sums gave a consistent and expected high dielectric behavior of the solvent. The main goal of this study is to estimate pKa shifts of proteins using large scale simulations of macromolecules in solution that do not suffer from artifacts arising from force truncation. As part of this project, we plan to use explicit solvent simulations of the electrostatic properties of small organics and proteins to parameterize a consistent set of continuum dielectric model parameters.