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Conformational entropy in molecular recognition by proteins

Nature volume 448, pages 325–329 (2007)Cite this article

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.

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Figure 1: Thermodynamic origins of high-affinity binding of target domains by calmodulin.
Figure 2: Correlation of the change in conformational entropy of calmodulin with the change in the total entropy of binding of a target domain.
Figure 3: Distribution of the amplitude of methyl-bearing side-chain motion of calmodulin in complex with target domains, and correlation with the change in total entropy of binding.

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Acknowledgements

This work was supported by a grant from the National Institutes of Health. We are grateful to S. W. Englander for helpful discussion and to Mark I. Greene for access to isothermal titration calorimetry instrumentation.

Author Contributions A.J.W. devised and initiated the project. K.K.F., M.S.M., and K.G.V. prepared the materials, collected and analysed the primary data. K.K.F. and A.J.W. performed the entropy analysis. A.J.W. wrote the manuscript.

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  1. Johnson Research Foundation and Department of Biochemistry & Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,

    Kendra King Frederick, Michael S. Marlow, Kathleen G. Valentine & A. Joshua Wand

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  1. Kendra King Frederick
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Correspondence to A. Joshua Wand.

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Frederick, K., Marlow, M., Valentine, K. et al. Conformational entropy in molecular recognition by proteins. Nature 448, 325–329 (2007). https://doi.org/10.1038/nature05959

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