Does the partial molar volume of a solute reflect the free energy of hydrophobic solvation?

https://doi.org/10.1016/j.molliq.2019.111527Get rights and content
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Highlights

  • Partial molar volume was determined for a series of halogenated benzotriazoles.

  • The excess volume results from solute-induced reorganization of the solvation shell.

  • Density of water in the hydration shell is lower than that of the bulky solvent.

  • Binding of halogenated benzotriazoles to hCK2α is driven by ligand hydrophobicity.

Abstract

Halogenated heterocyclic ligands are widely used as the potent and frequently selective inhibitors of protein kinases. However, the exact contribution of the hydrophobic solvation of a free ligand is rarely accounted for the balance of interactions contributing to the free energy of ligand binding. Herein, we propose a new experimental method based on volumetric data to estimate the hydrophobicity of a ligand. We have tested this approach for a series of ten variously halogenated benzotriazoles, the binding affinity of which to the target protein kinase CK2 was assessed with the use of thermal shift assay. According to the hierarchical clustering procedure, the excess volume, defined as the difference between the experimentally determined partial molar volume and the calculated in silico molecular volume, was found to be distant from any commonly used hydrophobicity descriptors of the ligand. The excess volume, however, properly predicts solute binding affinity. On the way, we have proved that the binding of halogenated benzotriazoles to the protein kinase CK2 is driven mostly by hydrophobic interactions.

Keywords

Partial molar volume
Hydrophobic effect
Halogenated benzotriazoles
Ligand binding
Thermal shift assay
Chromatographic Hydrophobicity Index

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