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Interplay between Conformational Entropy and Solvation Entropy in Protein-Ligand Binding

Verteramo, Maria Luisa LU ; Stenström, Olof LU ; Ignjatović, Majda Misini LU ; Caldararu, Octav LU ; Olsson, Martin A. LU ; Manzoni, Francesco LU ; Leffler, Hakon LU ; Oksanen, Esko LU ; Logan, Derek T. LU and Nilsson, Ulf J. LU , et al. (2019) In Journal of the American Chemical Society 141(5). p.2012-2026
Abstract

Understanding the driving forces underlying molecular recognition is of fundamental importance in chemistry and biology. The challenge is to unravel the binding thermodynamics into separate contributions and to interpret these in molecular terms. Entropic contributions to the free energy of binding are particularly difficult to assess in this regard. Here we pinpoint the molecular determinants underlying differences in ligand affinity to the carbohydrate recognition domain of galectin-3, using a combination of isothermal titration calorimetry, X-ray crystallography, NMR relaxation, and molecular dynamics simulations followed by conformational entropy and grid inhomogeneous solvation theory (GIST) analyses. Using a pair of diastereomeric... (More)

Understanding the driving forces underlying molecular recognition is of fundamental importance in chemistry and biology. The challenge is to unravel the binding thermodynamics into separate contributions and to interpret these in molecular terms. Entropic contributions to the free energy of binding are particularly difficult to assess in this regard. Here we pinpoint the molecular determinants underlying differences in ligand affinity to the carbohydrate recognition domain of galectin-3, using a combination of isothermal titration calorimetry, X-ray crystallography, NMR relaxation, and molecular dynamics simulations followed by conformational entropy and grid inhomogeneous solvation theory (GIST) analyses. Using a pair of diastereomeric ligands that have essentially identical chemical potential in the unbound state, we reduced the problem of dissecting the thermodynamics to a comparison of the two protein-ligand complexes. While the free energies of binding are nearly equal for the R and S diastereomers, greater differences are observed for the enthalpy and entropy, which consequently exhibit compensatory behavior, Δ ΔH°(R - S) = -5 ± 1 kJ/mol and -T Δ ΔS°(R - S) = 3 ± 1 kJ/mol. NMR relaxation experiments and molecular dynamics simulations indicate that the protein in complex with the S-stereoisomer has greater conformational entropy than in the R-complex. GIST calculations reveal additional, but smaller, contributions from solvation entropy, again in favor of the S-complex. Thus, conformational entropy apparently dominates over solvation entropy in dictating the difference in the overall entropy of binding. This case highlights an interplay between conformational entropy and solvation entropy, pointing to both opportunities and challenges in drug design.

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Journal of the American Chemical Society
volume
141
issue
5
pages
2012 - 2026
publisher
The American Chemical Society
external identifiers
  • scopus:85060535141
ISSN
0002-7863
DOI
10.1021/jacs.8b11099
language
English
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yes
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eb020fd0-ab65-413e-9da8-c3f70d034755
date added to LUP
2019-02-06 14:18:53
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2019-02-27 05:12:26
@article{eb020fd0-ab65-413e-9da8-c3f70d034755,
  abstract     = {<p>Understanding the driving forces underlying molecular recognition is of fundamental importance in chemistry and biology. The challenge is to unravel the binding thermodynamics into separate contributions and to interpret these in molecular terms. Entropic contributions to the free energy of binding are particularly difficult to assess in this regard. Here we pinpoint the molecular determinants underlying differences in ligand affinity to the carbohydrate recognition domain of galectin-3, using a combination of isothermal titration calorimetry, X-ray crystallography, NMR relaxation, and molecular dynamics simulations followed by conformational entropy and grid inhomogeneous solvation theory (GIST) analyses. Using a pair of diastereomeric ligands that have essentially identical chemical potential in the unbound state, we reduced the problem of dissecting the thermodynamics to a comparison of the two protein-ligand complexes. While the free energies of binding are nearly equal for the R and S diastereomers, greater differences are observed for the enthalpy and entropy, which consequently exhibit compensatory behavior, Δ ΔH°(R - S) = -5 ± 1 kJ/mol and -T Δ ΔS°(R - S) = 3 ± 1 kJ/mol. NMR relaxation experiments and molecular dynamics simulations indicate that the protein in complex with the S-stereoisomer has greater conformational entropy than in the R-complex. GIST calculations reveal additional, but smaller, contributions from solvation entropy, again in favor of the S-complex. Thus, conformational entropy apparently dominates over solvation entropy in dictating the difference in the overall entropy of binding. This case highlights an interplay between conformational entropy and solvation entropy, pointing to both opportunities and challenges in drug design.</p>},
  author       = {Verteramo, Maria Luisa and Stenström, Olof and Ignjatović, Majda Misini and Caldararu, Octav and Olsson, Martin A. and Manzoni, Francesco and Leffler, Hakon and Oksanen, Esko and Logan, Derek T. and Nilsson, Ulf J. and Ryde, Ulf and Akke, Mikael},
  issn         = {0002-7863},
  language     = {eng},
  number       = {5},
  pages        = {2012--2026},
  publisher    = {The American Chemical Society},
  series       = {Journal of the American Chemical Society},
  title        = {Interplay between Conformational Entropy and Solvation Entropy in Protein-Ligand Binding},
  url          = {http://dx.doi.org/10.1021/jacs.8b11099},
  volume       = {141},
  year         = {2019},
}