Conformational entropy in molecular recognition by proteins

Molecular recognition by proteins is fundamental to almost every biological process, particularly the protein associations underlying cellular signal transduction. Understanding the basis for protein–protein interactions requires the full characterization of the thermodynamics of their association. Historically it has been virtually impossible to experimentally estimate changes in protein conformational entropy, a potentially important component of the free energy of protein association. However, nuclear magnetic resonance spectroscopy has emerged as a powerful tool for characterizing the dynamics of proteins. Here we employ changes in conformational dynamics as a proxy for corresponding changes in conformational entropy. We find that the change in internal dynamics of the protein calmodulin varies significantly on binding a variety of target domains. Surprisingly, the apparent change in the corresponding conformational entropy is linearly related to the change in the overall binding entropy. This indicates that changes in protein conformational entropy can contribute significantly to the free energy of protein–ligand association. Understanding protein–protein interactions requires a full characterization of the thermodynamics of their association. In the past, it has been virtually impossible to experimentally estimate changes in protein conformational entropy, a potentially important component of the free energy of protein association. Frederick et al. have now used nuclear magnetic resonance spectroscopy to show that the change in internal dynamics of the protein calmodulin varies significantly upon binding a variety of target domains. This indicates that changes in protein conformational entropy can contribute significantly to the free energy of protein–ligand association Changes in residual protein entropy are a potentially important component of the change in the free energy of protein association, but such thermodynamics have been virtually impossible to determine experimentally. Here the authors used solution NMR spectroscopy to show that the change in internal dynamics of calmodulin varies significantly on binding a variety of target domains, which indicates that changes in residual protein conformational entropy can contribute significantly to the free energy of protein-ligand association.