Advanced

Protein Flexibility and Conformational Entropy in Ligand Design Targeting the Carbohydrate Recognition Domain of Galectin-3.

Diehl, Carl LU ; Engström, Olof; Delaine, Tamara LU ; Håkansson, Maria LU ; Genheden, Samuel LU ; Modig, Kristofer LU ; Leffler, Hakon LU ; Ryde, Ulf LU ; Nilsson, Ulf LU and Akke, Mikael LU (2010) In Journal of the American Chemical Society 132. p.14577-14589
Abstract
Rational drug design is predicated on knowledge of the three-dimensional structure of the protein-ligand complex and the thermodynamics of ligand binding. Despite the fundamental importance of both enthalpy and entropy in driving ligand binding, the role of conformational entropy is rarely addressed in drug design. In this work, we have probed the conformational entropy and its relative contribution to the free energy of ligand binding to the carbohydrate recognition domain of galectin-3. Using a combination of NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography, we characterized the binding of three ligands with dissociation constants ranging over 2 orders of magnitude. (15)N and (2)H spin relaxation measurements... (More)
Rational drug design is predicated on knowledge of the three-dimensional structure of the protein-ligand complex and the thermodynamics of ligand binding. Despite the fundamental importance of both enthalpy and entropy in driving ligand binding, the role of conformational entropy is rarely addressed in drug design. In this work, we have probed the conformational entropy and its relative contribution to the free energy of ligand binding to the carbohydrate recognition domain of galectin-3. Using a combination of NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography, we characterized the binding of three ligands with dissociation constants ranging over 2 orders of magnitude. (15)N and (2)H spin relaxation measurements showed that the protein backbone and side chains respond to ligand binding by increased conformational fluctuations, on average, that differ among the three ligand-bound states. Variability in the response to ligand binding is prominent in the hydrophobic core, where a distal cluster of methyl groups becomes more rigid, whereas methyl groups closer to the binding site become more flexible. The results reveal an intricate interplay between structure and conformational fluctuations in the different complexes that fine-tunes the affinity. The estimated change in conformational entropy is comparable in magnitude to the binding enthalpy, demonstrating that it contributes favorably and significantly to ligand binding. We speculate that the relatively weak inherent protein-carbohydrate interactions and limited hydrophobic effect associated with oligosaccharide binding might have exerted evolutionary pressure on carbohydrate-binding proteins to increase the affinity by means of conformational entropy. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of the American Chemical Society
volume
132
pages
14577 - 14589
publisher
The American Chemical Society
external identifiers
  • wos:000283276800053
  • pmid:20873837
  • scopus:77958035712
ISSN
1520-5126
DOI
10.1021/ja105852y
language
English
LU publication?
yes
id
36d74475-c30b-48e6-9709-f8d4bbf68c6a (old id 1687773)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20873837?dopt=Abstract
date added to LUP
2010-10-07 15:50:12
date last changed
2018-09-16 04:03:05
@article{36d74475-c30b-48e6-9709-f8d4bbf68c6a,
  abstract     = {Rational drug design is predicated on knowledge of the three-dimensional structure of the protein-ligand complex and the thermodynamics of ligand binding. Despite the fundamental importance of both enthalpy and entropy in driving ligand binding, the role of conformational entropy is rarely addressed in drug design. In this work, we have probed the conformational entropy and its relative contribution to the free energy of ligand binding to the carbohydrate recognition domain of galectin-3. Using a combination of NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography, we characterized the binding of three ligands with dissociation constants ranging over 2 orders of magnitude. (15)N and (2)H spin relaxation measurements showed that the protein backbone and side chains respond to ligand binding by increased conformational fluctuations, on average, that differ among the three ligand-bound states. Variability in the response to ligand binding is prominent in the hydrophobic core, where a distal cluster of methyl groups becomes more rigid, whereas methyl groups closer to the binding site become more flexible. The results reveal an intricate interplay between structure and conformational fluctuations in the different complexes that fine-tunes the affinity. The estimated change in conformational entropy is comparable in magnitude to the binding enthalpy, demonstrating that it contributes favorably and significantly to ligand binding. We speculate that the relatively weak inherent protein-carbohydrate interactions and limited hydrophobic effect associated with oligosaccharide binding might have exerted evolutionary pressure on carbohydrate-binding proteins to increase the affinity by means of conformational entropy.},
  author       = {Diehl, Carl and Engström, Olof and Delaine, Tamara and Håkansson, Maria and Genheden, Samuel and Modig, Kristofer and Leffler, Hakon and Ryde, Ulf and Nilsson, Ulf and Akke, Mikael},
  issn         = {1520-5126},
  language     = {eng},
  pages        = {14577--14589},
  publisher    = {The American Chemical Society},
  series       = {Journal of the American Chemical Society},
  title        = {Protein Flexibility and Conformational Entropy in Ligand Design Targeting the Carbohydrate Recognition Domain of Galectin-3.},
  url          = {http://dx.doi.org/10.1021/ja105852y},
  volume       = {132},
  year         = {2010},
}