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Interplay between Conformational Entropy and Solvation Entropy in Protein-Ligand Binding
Maria Luisa Verteramo1, Olof Stenström2, Majda Misini Ignjatović3
1Centre for Analysis and Synthesis, Department of Chemistry , Lund University , 221 00 Lund , Sweden.
Journal of the American Chemical Society
|January 9, 2019
Summary
Understanding molecular recognition requires dissecting binding thermodynamics. This study reveals conformational entropy, not solvation entropy, dominates differences in ligand binding affinity to galectin-3, offering insights for drug design.
Area of Science:
- Biochemistry and Molecular Biology
- Chemical Thermodynamics
- Structural Biology
Background:
- Molecular recognition is crucial in chemistry and biology, but dissecting binding thermodynamics, especially entropic contributions, remains challenging.
- Galectin-3's carbohydrate recognition domain is a key target for understanding these interactions.
- Accurate assessment of entropic contributions is vital for interpreting binding events at a molecular level.
Purpose of the Study:
- To elucidate the molecular determinants of ligand affinity differences in the galectin-3 carbohydrate recognition domain.
- To quantitatively assess the contributions of enthalpy and entropy to binding free energy.
- To differentiate the roles of conformational and solvation entropy in protein-ligand interactions.
Main Methods:
- Isothermal titration calorimetry (ITC) for binding thermodynamics.
- X-ray crystallography for structural determination.
- NMR relaxation and molecular dynamics (MD) simulations for conformational dynamics.
- Grid Inhomogeneous Solvation Theory (GIST) for solvation free energy analysis.
Main Results:
- Diastereomeric ligands with similar unbound chemical potentials were used to isolate binding differences.
- Enthalpy and entropy showed compensatory behavior, with ΔΔH°(R - S) = -5 ± 1 kJ/mol and -TΔΔS°(R - S) = 3 ± 1 kJ/mol.
- The S-stereoisomer complex exhibited greater protein conformational entropy than the R-stereoisomer complex.
- GIST calculations indicated smaller, favorable solvation entropy contributions for the S-complex.
Conclusions:
- Conformational entropy plays a dominant role over solvation entropy in differentiating ligand binding affinity to galectin-3.
- The interplay between conformational and solvation entropy presents both opportunities and challenges in rational drug design.
- This study provides a detailed molecular understanding of entropic contributions to binding thermodynamics.
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