Dynamics of protein-protein docking: cytochrome c and cytochrome c peroxidase revisited.

The dynamics of the docking step in the electron transfer reaction between yeast cytochrome c peroxidase and iso-1-cytochrome c has been studied using the Brownian dynamics method. In particular we have calculated the bimolecular rate constant at which a specific complex, the xray crystalline complex, can form in solution by translational and rotational diffusion in a field of force. Complexation criteria have been assessed based on the simultaneous alignment of three atom-atom contacts, as well as alternative criteria. The proteins are able to align one or two contacts at remarkably high rates, in fact, at rates approaching the diffusion-controlled limit for two spheres reactive over their entire surfaces. Three contacts may align, and hence the specific complex may dock, at rates on the order of 10(8) M(-1) s(-1), which is quite representative of the experimental association rate constant for ET-competent complex(es). The formation of the specific complex is strongly influenced by the favorable electrostatic interaction between these proteins. It is striking that a specific protein-protein complex can form within one order of magnitude as fast as two spherical proteins can touch at any orientation. It remains plausible that the high ET tunneling rate in this system can take place through a single highly favorable specific complex using a single high efficiency pathway. Still the contribution from a nonspecific set of complexes is not ruled out, particularly considering the marginal reproduction of the ionic strength dependence in the formation of the xray complex.