title: How Can Hydrophobic Association Be Enthalpy Driven?
abstract: Hydrophobic association is often recognized as being driven by favorable entropic contributions. Here, using explicit solvent molecular dynamics simulations we investigate binding in a model hydrophobic receptor-ligand system which appears, instead, to be driven by enthalpy and opposed by entropy. We use the temperature dependence of the potential of mean force to analyze the thermodynamic contributions along the association coordinate. Relating such contributions to the ongoing changes in system hydration allows us to demonstrate that the overall binding thermodynamics is determined by the expulsion of disorganized water from the receptor cavity. Our model study sheds light on the solvent-induced driving forces for receptor-ligand association of general, transferable relevance for biological systems with poorly hydrated binding sites.
authors.affiliation: Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, Howard Hughes Medical Institute, Department of Pharmacology, University of California, San Diego and Physics Department, Technical University Munich, 85748 Garching, Germany.
authors.forename: Piotr
authors.initials: P
authors.lastname: Setny
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baron
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon