The proposed study will develop and employ theoretical methods to investigate protein-protein and protein-DNA association phenomena in aqueous media, dealing with both equilibrium and dynamical aspects. Attention will be especially directed toward the crucial solvent and electrolyte effects which mediate macromolecular interactions in physiological aqueous solutions. Specific projects include: (i) A study of protein-protein electrostatic interactions, with the development and application of several strategies which will allow the rapid computation of accurate protein-protein (and protein-nucleic acid) electrostatic interaction potentials to benefit Brownian dynamics simulations and other automated docking procedures requiring rapid calculation of energies from look-up tables; (ii) The continued refinement and testing of the Brownian dynamics simulation method by the inclusion and evaluation of limited surface atom flexibility and empirical methods for rapid computation of electrostatic forces. (Application will be made to association and electron transfer reactions in the cytochromes and mutants to further our understanding of the role of a variety of influences on cytochrome electron transfer); iii) Simulation of nonspecific binding of genome regulatory proteins to DNA by an adaptation of existing Brownian dynamics methodology to study nonspecific protein-DNA associations. (Dynamical aspects of nonspecific binding of cro repressor protein and the E. coli catabolite gene activator protein to B-DNA will be studied); and iv) Development of software for systematic searching of optimum docking conformations of protein-protein and protein-DNA complexes, allowing an automated force-guided exhaustive search of docked conformers which would avoid trapping in local energy minima with user-intervention.