BROWNIAN DYNAMICS SIMULATION OF PROTEIN-PROTEIN DIFFUSIONAL ENCOUNTER

Protein association events are ubiquitous in biological systems. Some protein associations and subsequent responses are diffusion controlled in vivo. Hence, it is important to be able to compute bimolecular dif fusional association rates for proteins. The Brownian dynamics simulat ion methodology may be used to simulate protein-protein encounter, com pute association rates, and examine their dependence on protein mutati on and the nature of the physical environment (e.g., as a function of ionic strength or viscosity). Here, the theory for Brownian dynamics s imulations is described, and important methodological aspects, particu larly pertaining to the correct modeling of electrostatic forces and d efinition of encounter complex formation, are highlighted. To illustra te application of the method, simulations of the diffusional encounter of the extracellular ribonuclease, barnase, and its intracellular inh ibitor, barstar, are described. This shows how experimental rates for a series of mutants and the dependence of rates on ionic strength can be reproduced well by Brownian dynamics simulations. Potential future uses of the Brownian dynamics method for investigating protein-protein association are discussed. (C) 1998 Academic Press.