Brownian dynamics simulation of protein association

Summary The Brownian Dynamics (BD) method is applied to study the diffusive dynamics and interaction of two proteins, cytochrome c (CYTC) and cytochrome c peroxidase (CYP). We examine the role of protein electrostatic charge distribution in the facilitation of protein-protein docking prior to the electron transfer step, assessing the influence of individual charged amino acid residues. Accurate interaction potentials are computed by iterating the linearized Poisson-Boltzmann (PB) equation around the larger protein CYP. The low dielectric constant inside proteins, electrolyte screening effects and irregular protein surface topography are taken into account. We observe a large ensemble of electrostatically stable encounter complexes seemingly with acceptable geometric requirements for electron transfer rather than a single dominant complex. Stabilities of the large variety of docking complexes are rationalized in terms of generalized charged residue complementarities. However, it is found that the electrostatic interactions giving rise to complex stabilities are somewhat nonspecific in nature. A large series of additional simulations are performed in which individual charged residues on CYTC have been chemically modified. Resulting perturbations of the association rate are significant and qualitatively similar to results observed in comparable kinetics experiments. We therefore demonstrate the potential of the Brownian dynamics method to estimate the effects of site-directed mutagenesis on protein-protein and protein-ligand diffusional association rates.