Kinetics of desolvation-mediated protein-protein binding

The role of desolvation in protein binding kinetics is investigated using B rownian dynamics simulations in complexes in which the electrostatic intera ctions are relatively weak, We find that partial desolvation, modeled by a short-range atomic contact potential, is not only a major contributor to th e binding free energy but also substantially increases the diffusion-limite d rate for complexes in which long-range electrostatics is weak. This rate enhancement is mostly due to weakly specific pathways leading to a low free -energy attractor, i.e,, a precursor state before docking. For alpha-chymot rypsin and human leukocyte elastase, both interacting with turkey ovomucoid third domain, we find that the forward rate constant associated with a col lision within a solid angle cp around their corresponding attractor approac hes 10(7) and 10(6) M(-1)s(-1) respectively, in the limit phi similar to 2 degrees. Because these estimates agree well with experiments, we conclude t hat the final bound conformation must be preceded by a small set of well-de fined diffusion-accessible precursor states. The inclusion of the otherwise repulsive desolvation interaction also explains the lack of aggregation in proteins by restricting nonspecific association times to similar to 4 ns. Under the same reaction conditions but without short range forces, the asso ciation rate would be only similar to 10(3) M(-1)s(-1). Although desolvatio n increases these rates by three orders of magnitude, desolvation-mediated association is still at least 100-fold slower than the electrostatically as sisted binding in complexes such as barnase and barstar.