Protein Association in Dilute and Crowded Solutions

Most biological processes are mediated by mediated by protein association, and often are under kinetic rather than thermodynamic control. We have developed the transient-complex theory for protein association, which presents a framework for elucidating the mechanisms of protein association and for predicting the association rates. The transient complex refers to an intermediate along the association process, in which the two associating molecules have near-native separation and relative orientation but have yet to form the short-range specific interactions of the native complex. Our theory rationalizes the variations in association rates over 10 orders of magnitudes and gives accurate prediction of the association rates based on the structures of the native complexes. In the cellular context, association processes occur in the presence of a high concentration of background macromolecules. We have developed methods to model the effects of the crowded cellular environments on the affinities and rate constants of protein association. These studies allow us to achieve a quantitative understanding of biological processes in the cellular context, based on fundamental physical principles.