Realistic protein–protein association rates from a simple diffusional model neglecting long‐range interactions, free energy barriers, and landscape ruggedness

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 104–106 M−1 sec−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 105–106 M−1 sec−1 range, 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.