Disparate ionic-strength dependencies of on and off rates in protein-protein association

Electrostatic interactions have been observed to play important roles in the kinetics of protein-protein association. Ionic strength, by its ability to modulate the magnitude of electrostatic interactions, has often been conveniently used to test their presence. From experiments on a wide range of associating proteins, a common feature has emerged: the on rates show strong dependence on ionic strength whereas the off rates are relatively insensitive. Here this feature is explained by an explicit description of a transition state for the association process and the suggestion that this transition is near the final bound state of two proteins. The molecular basis of the transition state in the bimolecular process lies in the fact that the bound state is characterized by local specific (e.g., van der Waals, hydrophobic, and electrostatic) interactions, whereas the unbound state is characterized by translational and rotational freedom. In the transition state the protein-protein pair encounters a free-energy maximum since its translational-rotational entropy is reduced while the specific interactions are not yet attained. In this formalism of the protein-protein association process, the enhancement of on rates by long-range electrostatic interactions can be written (analogous to an ordinary transition-state theory) in the form k(on) = k(0)(on)exp(-G(el)/k(B)T), where G(el) is the electrostatic free energy of the transition state.