The role of conformational entropy in molecular recognition by calmodulin

Johnson Research Foundation, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nature Chemical Biology (Impact Factor: 13.22). 04/2010; 6(5):352-8. DOI: 10.1038/nchembio.347
Source: PubMed

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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Available from: Andrew Joshua Wand, Aug 15, 2015
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    • "For example, reorganization of the hydrogen bonding networks and solvent bridges of the interacting molecules upon mutation, which was accompanied only by subtle structural changes, leads to radically different binding free energy [3] [4]. A recent work [5] shows that the apparent change in the amino acid dynamics determined by NMR spectroscopy is linearly related to the change in the overall binding entropy and also that changes in side-chain dynamics determined from NMR data can be used as a quantitative estimate of changes in conformational entropy [6] [7]. Also, an analysis of crystallographic B-factors has revealed a significant decrease of flexibility of residues exposed to solvent compared to flexibility of residues interacting with another biomolecule and further compared to their flexibility in the protein core [8]. "
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    • "Intrinsic internal dynamics and conformational entropy in proteins and protein:protein interfaces can modulate binding affinities and binding modes (Huang and Montelione, 2005), particularly in systems featuring promiscuous interactions (Nobeli et al., 2009; Perkins et al., 2010; Schreiber and Keating, 2011). In fact, elegant methyl relaxation studies revealed that these phenomena are intimately correlated with modulation of molecular recognition by calmodulin (Marlow et al., 2010) and the catabolite activator protein (Tzeng and Kalodimos, 2012). In our work, we observe exchange broadening on a slower (microsecond ) time scale specifically at a protein:protein interface. "
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