Enthalpy/entropy compensation effects from cavity desolvation underpin broad ligand binding selectivity for rat odorant binding protein 3
2014
Portman, Katherine L. | Long, Jed | Carr, Stephen | Briand, Loïc | Winzor, Donald J. | Searle, Mark S. | Scott, David J. | National Centre for Macromolecular Hydrodynamics, School of Biosciences - School of Chemistry, Centre for Biomolecular Sciences ; University of Nottingham, UK (UON) | School of Chemistry, Centre for Biomolecular Sciences ; University of Nottingham, UK (UON) | ISIS Neutron and Muon Source (ISIS) ; STFC Rutherford Appleton Laboratory (RAL) ; Science and Technology Facilities Council (STFC)-Science and Technology Facilities Council (STFC) | Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA) ; Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS) | School of Chemistry and Molecular Biosciences ; University of Southern Queensland (USQ) | Neutron and Muon Source and Research Complex at Harwell ; STFC Rutherford Appleton Laboratory (RAL) ; Science and Technology Facilities Council (STFC)-Science and Technology Facilities Council (STFC) | National Centre for Macromolecular Hydrodynamics, School of Biosciences ; University of Nottingham, UK (UON) | Biotechnology and Biological Sciences Research Council (UK) [BB/D522870/1]; BBSRC DTA; Medical Research Council (UK); BBSKC (UK); Science and Technology Facilities Council; University of Nottingham
Evolution has produced proteins with exquisite ligand binding specificity, and manipulating this effect has been the basis for much of modern rational drug design. However, there are general classes of proteins with broader ligand selectivity linked to function, the origin of which is poorly understood. The odorant binding proteins (OBPs) sequester volatile molecules for transportation to the olfactory receptors. Rat OBP3, which we characterize by X-ray crystallography and NMR, binds a homologous series of aliphatic gamma-lactones within its aromatic-rich hydrophobic pocket with remarkably little variation in affinity but extensive enthalpy/entropy compensation effects. We show that the binding energetics are modulated by two desolvation processes with quite different thermodynamic signatures. Ligand desolvation follows the classical hydrophobic effect; however, cavity desolvation is consistent with the liberation of "high energy" water molecules back into bulk solvent with a strong, but compensated, enthalpic contribution, which together. underpin the origins of broad ligand binding selectivity.
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