Biophys J, March 2000, p. 1094-1105, Vol. 78, No. 3

Kinetics of Desolvation-Mediated Protein-Protein Binding

Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, USA

The role of desolvation in protein binding kinetics is investigated using Brownian dynamics simulations in complexes in which the electrostatic interactions are relatively weak. We find that partial desolvation, modeled by a short-range atomic contact potential, is not only a major contributor to the binding free energy but also substantially increases the diffusion-limited 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 -chymotrypsin and human leukocyte elastase, both interacting with turkey ovomucoid third domain, we find that the forward rate constant associated with a collision within a solid angle  around their corresponding attractor approaches 10⁷ and 10⁶ M¹s¹, respectively, in the limit  ~ 2°. Because these estimates agree well with experiments, we conclude that the final bound conformation must be preceded by a small set of well-defined 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 ~4 ns. Under the same reaction conditions but without short range forces, the association rate would be only ~10³ M¹s¹. Although desolvation increases these rates by three orders of magnitude, desolvation-mediated association is still at least 100-fold slower than the electrostatically assisted binding in complexes such as barnase and barstar.

Biophys J, March 2000, p. 1094-1105, Vol. 78, No. 3
© 2000 by the Biophysical Society   0006-3495/00/03/1094/12  $2.00

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