Protein conformational dynamics can be critical for ligand binding in two ways that relate to kinetics and thermodynamics respectively. First, conformational transitions between different substates can control access to the binding site (kinetics). Secondly, differences between free and ligand-bound states in their conformational fluctuations contribute to the entropy of ligand binding (thermodynamics). In the present paper, I focus on the second topic, summarizing our recent results on the role of conformational entropy in ligand binding to Gal3C (the carbohydrate-recognition domain of galectin-3). NMR relaxation experiments provide a unique probe of conformational entropy by characterizing bond-vector fluctuations at atomic resolution. By monitoring differences between the free and ligand-bound states in their backbone and side chain order parameters, we have estimated the contributions from conformational entropy to the free energy of binding. Overall, the conformational entropy of Gal3C increases upon ligand binding, thereby contributing favourably to the binding affinity. Comparisons with the results from isothermal titration calorimetry indicate that the conformational entropy is comparable in magnitude to the enthalpy of binding. Furthermore, there are significant differences in the dynamic response to binding of different ligands, despite the fact that the protein structure is virtually identical in the different protein–ligand complexes. Thus both affinity and specificity of ligand binding to Gal3C appear to depend in part on subtle differences in the conformational fluctuations that reflect the complex interplay between structure, dynamics and ligand interactions.
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Conference Article|
March 21 2012
Conformational dynamics and thermodynamics of protein–ligand binding studied by NMR relaxation
Mikael Akke
Mikael Akke
1
1Department of Biophysical Chemistry, Center for Molecular Protein Science, Lund University, PO Box 124, SE-221 00 Lund, Sweden
1emailmikael.akke@bpc.lu.se
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Publisher: Portland Press Ltd
Received:
October 05 2011
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem Soc Trans (2012) 40 (2): 419–423.
Article history
Received:
October 05 2011
Citation
Mikael Akke; Conformational dynamics and thermodynamics of protein–ligand binding studied by NMR relaxation. Biochem Soc Trans 1 April 2012; 40 (2): 419–423. doi: https://doi.org/10.1042/BST20110750
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