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.