Brownian Dynamics Simulation of Protein–Protein Diffusional Encounter

Protein association events are ubiquitous in biological systems. Some protein associations and subsequent responses are diffusion controlledin vivo.Hence, it is important to be able to compute bimolecular diffusional association rates for proteins. The Brownian dynamics simulation methodology may be used to simulate protein–protein encounter, compute association rates, and examine their dependence on protein mutation and the nature of the physical environment (e.g., as a function of ionic strength or viscosity). Here, the theory for Brownian dynamics simulations is described, and important methodological aspects, particularly pertaining to the correct modeling of electrostatic forces and definition of encounter complex formation, are highlighted. To illustrate application of the method, simulations of the diffusional encounter of the extracellular ribonuclease, barnase, and its intracellular inhibitor, 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.