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Entropy–Entropy Compensation between the Protein, Ligand, and Solvent Degrees of Freedom Fine-Tunes Affinity in Ligand Binding to Galectin-3C

Wallerstein, Johan LU ; Ekberg, Vilhelm LU ; Misini Ignjatović, Majda LU ; Kumar, Rohit LU ; Caldararu, Octav LU ; Peterson, Kristoffer LU ; Wernersson, Sven LU ; Brath, Ulrika LU ; Leffler, Hakon LU and Oksanen, Esko LU , et al. (2021) In Journal of the American Chemical Society 1(4). p.484-500
Abstract
Molecular recognition is fundamental to biological signaling. A central question is how individual interactions between molecular moieties affect the thermodynamics of ligand binding to proteins and how these effects might propagate beyond the immediate neighborhood of the binding site. Here, we investigate this question by introducing minor changes in ligand structure and characterizing the effects of these on ligand affinity to the carbohydrate recognition domain of galectin-3, using a combination of isothermal titration calorimetry, X-ray crystallography, NMR relaxation, and computational approaches including molecular dynamics (MD) simulations and grid inhomogeneous solvation theory (GIST). We studied a congeneric series of ligands... (More)
Molecular recognition is fundamental to biological signaling. A central question is how individual interactions between molecular moieties affect the thermodynamics of ligand binding to proteins and how these effects might propagate beyond the immediate neighborhood of the binding site. Here, we investigate this question by introducing minor changes in ligand structure and characterizing the effects of these on ligand affinity to the carbohydrate recognition domain of galectin-3, using a combination of isothermal titration calorimetry, X-ray crystallography, NMR relaxation, and computational approaches including molecular dynamics (MD) simulations and grid inhomogeneous solvation theory (GIST). We studied a congeneric series of ligands with a fluorophenyl-triazole moiety, where the fluorine substituent varies between the ortho, meta, and para positions (denoted O, M, and P). The M and P ligands have similar affinities, whereas the O ligand has 3-fold lower affinity, reflecting differences in binding enthalpy and entropy. The results reveal surprising differences in conformational and solvation entropy among the three complexes. NMR backbone order parameters show that the O-bound protein has reduced conformational entropy compared to the M and P complexes. By contrast, the bound ligand is more flexible in the O complex, as determined by 19F NMR relaxation, ensemble-refined X-ray diffraction data, and MD simulations. Furthermore, GIST calculations indicate that the O-bound complex has less unfavorable solvation entropy compared to the other two complexes. Thus, the results indicate compensatory effects from ligand conformational entropy and water entropy, on the one hand, and protein conformational entropy, on the other hand. Taken together, these different contributions amount to entropy–entropy compensation among the system components involved in ligand binding to a target protein. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Conformational entropy, Drug design, Ligand binding specificity, Molecular recognition, Solvation entropy, Thermodynamics
in
Journal of the American Chemical Society
volume
1
issue
4
pages
17 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:34467311
  • scopus:85111222814
  • scopus:85111222814
ISSN
0002-7863
DOI
10.1021/jacsau.0c00094
language
English
LU publication?
yes
id
a924bb95-ad56-4664-9b89-72e719a29214
date added to LUP
2021-06-15 11:27:35
date last changed
2024-06-13 16:54:17
@article{a924bb95-ad56-4664-9b89-72e719a29214,
  abstract     = {{Molecular recognition is fundamental to biological signaling. A central question is how individual interactions between molecular moieties affect the thermodynamics of ligand binding to proteins and how these effects might propagate beyond the immediate neighborhood of the binding site. Here, we investigate this question by introducing minor changes in ligand structure and characterizing the effects of these on ligand affinity to the carbohydrate recognition domain of galectin-3, using a combination of isothermal titration calorimetry, X-ray crystallography, NMR relaxation, and computational approaches including molecular dynamics (MD) simulations and grid inhomogeneous solvation theory (GIST). We studied a congeneric series of ligands with a fluorophenyl-triazole moiety, where the fluorine substituent varies between the <i>ortho</i>, <i>meta</i>, and <i>para </i>positions (denoted O, M, and P). The M and P ligands have similar affinities, whereas the O ligand has 3-fold lower affinity, reflecting differences in binding enthalpy and entropy. The results reveal surprising differences in conformational and solvation entropy among the three complexes. NMR backbone order parameters show that the O-bound protein has reduced conformational entropy compared to the M and P complexes. By contrast, the bound ligand is more flexible in the O complex, as determined by <sup>19</sup>F NMR relaxation, ensemble-refined X-ray diffraction data, and MD simulations. Furthermore, GIST calculations indicate that the O-bound complex has less unfavorable solvation entropy compared to the other two complexes. Thus, the results indicate compensatory effects from ligand conformational entropy and water entropy, on the one hand, and protein conformational entropy, on the other hand. Taken together, these different contributions amount to entropy–entropy compensation among the system components involved in ligand binding to a target protein.}},
  author       = {{Wallerstein, Johan and Ekberg, Vilhelm and Misini Ignjatović, Majda and Kumar, Rohit and Caldararu, Octav and Peterson, Kristoffer and Wernersson, Sven and Brath, Ulrika and Leffler, Hakon and Oksanen, Esko and Logan, Derek T. and Nilsson, Ulf J. and Ryde, Ulf and Akke, Mikael}},
  issn         = {{0002-7863}},
  keywords     = {{Conformational entropy; Drug design; Ligand binding specificity; Molecular recognition; Solvation entropy; Thermodynamics}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{484--500}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of the American Chemical Society}},
  title        = {{Entropy–Entropy Compensation between the Protein, Ligand, and Solvent Degrees of Freedom Fine-Tunes Affinity in Ligand Binding to Galectin-3C}},
  url          = {{http://dx.doi.org/10.1021/jacsau.0c00094}},
  doi          = {{10.1021/jacsau.0c00094}},
  volume       = {{1}},
  year         = {{2021}},
}