Conformational entropy in molecular recognition by proteins

Abstract

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.

Macromolecular semi-rigid nanocavities for cooperative recognition of specific large molecular shapes

“…Similar to the literature 5,13,53,54 , the host-guest system under discussion showed a good linear correlation (correlation coefficient: r ¼ 0.98) between DH°and TDS° (Supplementary Fig. S4).…”

Automated electron‐density sampling reveals widespread conformational polymorphism in proteins

“…Such changes have been proposed to dominate the overall entropy of peptide binding and underlie the compensation of entropic and enthalpic contributions to peptide recognition. 2 In general, the unmodeled alternate conformations identified by Ringer help explain the observed conformational plasticity of the CaM binding site and provide testable hypotheses about where residual side-chain entropy is distributed in the protein.…”

NMR reveals novel mechanisms of protein activity regulation

“…By studying calmodulin in complex with a series of different binding peptides, it was found that the apparent change in conformational entropy was linearly related to the change in the overall binding entropy. 60 This observation provided strong evidence that changes in protein conformational entropy can contribute significantly to the energetics of proteinligand association. In fact, empirical calibration of the NMR-derived conformational entropy suggested that the standard approach of summing up the individual contribution of each one of the experimentally accessible bond vectors may in fact underestimate the overall contribution of conformational entropy to the binding free energy.…”

“…Very interesting results on calmodulin have been particularly revealing about the role of conformational entropy in molecular recognition and allostery. 60,61 Calmodulin, a central player in calcium-mediated signaling, has been used as a model system to investigate the role of changes in fast (subnanosecond) internal dynamics and its associated conformational entropy in protein-ligand binding. By studying calmodulin in complex with a series of different binding peptides, it was found that the apparent change in conformational entropy was linearly related to the change in the overall binding entropy.…”