  We develop a simple but rigorous model of protein-protein association
kinetics based on diffusional association on free energy landscapes obtained by
sampling configurations within and surrounding the native complex binding
funnels. Guided by results obtained on exactly solvable model problems, we
transform the problem of diffusion in a potential into free diffusion in the
presence of an absorbing zone spanning the entrance to the binding funnel. The
free diffusion problem is solved using a recently derived analytic expression
for the rate of association of asymmetrically oriented molecules. Despite the
required high steric specificity and the absence of long-range attractive
interactions, the computed rates are typically on the order of 10^4-10^6 M-1
s-1, several orders of magnitude higher than rates obtained using a purely
probabilistic model in which the association rate for free diffusion of
uniformly reactive molecules is multiplied by the probability of a correct
alignment of the two partners in a random collision. As the association rates
of many protein-protein complexes are also in the 10^5-10^6 M-1 s-1, our
results suggest that free energy barriers arising from desolvation and/or
side-chain freezing during complex formation or increased ruggedness within the
binding funnel, which are completely neglected in our simple diffusional model,
do not contribute significantly to the dynamics of protein-protein association.
The transparent physical interpretation of our approach that computes
association rates directly from the size and geometry of protein-protein
binding funnels makes it a useful complement to Brownian dynamics simulations.
