Ligand Binding, Protein Fluctuations, And Allosteric Free Energy

Although the importance of protein dynamics in protein function is generally recognized, the role of protein fluctuations in allosteric effects scarcely has been considered. To address this gap, the Kullback‐Leibler divergence (Dx) between protein conformational distributions before and after ligand binding was proposed as a means of quantifying allosteric effects in proteins. Here, previous applications of Dx to methods for analysis and simulation of proteins are first reviewed, and their implications for understanding aspects of protein function and protein evolution are discussed. Next, equations for Dx suggest that kBTDx should be interpreted as an allosteric free energy — the free energy associated with changing the ligand‐free protein conformational distribution to the ligand‐bound conformational distribution. This interpretation leads to a thermodynamic model of allosteric transitions that unifies existing perspectives on the relation between ligand binding and changes in protein conformational dis...