Prediction of Protein-Protein Association Rates from a Transition-State Theory

SummaryWe recently developed a theory for the rates of protein-protein association. The theory is based on the concept of a transition state, which separates the bound state, with numerous short-range interactions but restricted translational and rotational freedom, and the unbound state, with, at most, a small number of interactions but expanded configurational freedom. When not accompanied by large-scale conformational changes, protein-protein association becomes diffusion limited. The association rate is then predicted as ka=ka0exp(−ΔGel‡/kBT), where ΔGel‡ is the electrostatic interaction free energy in the transition state, ka0 is the rate in the absence of electrostatic interactions, and kBT is thermal energy. Here, this transition-state theory is used to predict the association rates of four protein complexes. The predictions for the wild-type complexes and 23 mutants are found to agree closely with experimental data over wide ranges of ionic strength