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Conformational dynamics and thermodynamics of protein-ligand binding studied by NMR relaxation.

Akke, Mikael LU (2012) In Biochemical Society Transactions 40(2). p.419-423
Abstract
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.... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Biochemical Society Transactions
volume
40
issue
2
pages
419 - 423
publisher
Biochemical Society
external identifiers
  • wos:000303624200020
  • pmid:22435823
  • scopus:84859332583
ISSN
0300-5127
DOI
10.1042/BST20110750
language
English
LU publication?
yes
id
a259d73a-f485-4d2d-9ffd-1eb39ab0acde (old id 2431578)
date added to LUP
2012-04-12 14:56:09
date last changed
2017-11-12 03:09:50
@article{a259d73a-f485-4d2d-9ffd-1eb39ab0acde,
  abstract     = {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.},
  author       = {Akke, Mikael},
  issn         = {0300-5127},
  language     = {eng},
  number       = {2},
  pages        = {419--423},
  publisher    = {Biochemical Society},
  series       = {Biochemical Society Transactions},
  title        = {Conformational dynamics and thermodynamics of protein-ligand binding studied by NMR relaxation.},
  url          = {http://dx.doi.org/10.1042/BST20110750},
  volume       = {40},
  year         = {2012},
}