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The role of conformational entropy in molecular recognition by calmodulin

Nature Chemical Biology volume 6, pages 352–358 (2010)Cite this article

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Abstract

The physical basis for high-affinity interactions involving proteins is complex and potentially involves a range of energetic contributions. Among these are changes in protein conformational entropy, which cannot yet be reliably computed from molecular structures. We have recently used changes in conformational dynamics as a proxy for changes in conformational entropy of calmodulin upon association with domains from regulated proteins. The apparent change in conformational entropy was linearly related to the overall binding entropy. This view warrants a more quantitative foundation. Here we calibrate an 'entropy meter' using an experimental dynamical proxy based on NMR relaxation and show that changes in the conformational entropy of calmodulin are a significant component of the energetics of binding. Furthermore, the distribution of motion at the interface between the target domain and calmodulin is surprisingly noncomplementary. These observations promote modification of our understanding of the energetics of protein-ligand interactions.

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Figure 1: Distribution of methyl symmetry axis generalized order parameters for the target domains bound to calcium-saturated wild-type calmodulin.
Figure 2: Dynamical character of the hydrophobic anchor in the N-terminal domain of CaM.
Figure 3: Calibration of the dynamical proxy for protein conformational entropy.
Figure 4: Decomposition of the entropy of binding of target domains to calcium-saturated calmodulin.

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Acknowledgements

We are grateful to S. Bédard, A. Seitz and J.K. Kranz of the University of Pennsylvania for preparation of isotopically labeled smMLCK(p) peptide. We thank K. Sharp for helpful discussion. Financial support was provided by the US National Institutes of Health (DK 39806). K.K.F. acknowledges financial support from the US National Institutes of Health (GM 08275). J.D. acknowledges financial support from the Wenner-Gren Foundations.

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Author notes

  1. Michael S Marlow and Jakob Dogan: These authors contributed equally to this work.

Authors and Affiliations

  1. Johnson Research Foundation, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Michael S Marlow, Jakob Dogan, Kendra K Frederick, Kathleen G Valentine & A Joshua Wand

  2. Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Michael S Marlow, Jakob Dogan, Kendra K Frederick, Kathleen G Valentine & A Joshua Wand

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  1. Michael S Marlow
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Contributions

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

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Correspondence to A Joshua Wand.

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Marlow, M., Dogan, J., Frederick, K. et al. The role of conformational entropy in molecular recognition by calmodulin. Nat Chem Biol 6, 352–358 (2010). https://doi.org/10.1038/nchembio.347

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