2866 J. Chem. Theory Comput. 2010, 6, 2866–2871 How Can Hydrophobic Association Be Enthalpy Driven? Piotr Setny,*,†,‡,¶ Riccardo Baron,*,†,¶ and J. Andrew McCammon† 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 Received June 5, 2010 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. 1. Introduction It is becoming widely recognized that water-the common environment for most biological processes-plays a signiﬁ- cant role in binding (thermo)dynamics, being far more important than just a passive, embedding medium. This is particularly relevant for hydrophobic interactions, in which water-related effects are typically regarded as the origin of the entropic driving force. Nevertheless, our knowledge about how water structure and dynamics evolve during such binding events and what are the underlying thermodynamic contributions is still sparse. One of the recent, key advances is the distinction among different length scales involved.1-4 It is now generally accepted that in the limit of small solutes, e.g., small hydrocarbons, the surrounding water structure and hydrogen bonding are not considerably affected. In this case, hydration thermodynamics appears to be dominated by the entropic effect of restricting spontaneous solvent ﬂuctuations to only those permitting the presence of the solute.5-8 The resulting * Corresponding authors. E-mail: piotr.setny@tum.de (P.S.), rbaron@mccammon.ucsd.edu (R.B.). † University of California, San Diego. ‡ Technical University Munich. ¶ These authors contributed equally to this work. solvent-mediated interactions, exempliﬁed by the well- investigated case of methane pair in water,9-12 display a characteristic, entropy-stabilized free energy minimum for the direct contact of two solutes. However, the spontaneous assembly of small isolated hydrophobic molecules is not observed,13 owing to a comparatively larger conﬁgurational volume of the solvent-separated pairs. Hydrophobic-driven association usually involves at least one interacting partner carrying an extended nonpolar region. It affects the hydrogen-bonding network of interfacial water molecules, inducing a variety of large-length scale hydro- phobic effects.14,15 The actual solvent behavior critically depends on the strength of solute-solvent attraction and varies from the persistent hydration of strongly interacting objects,16,17 through the formation of a thin vapor-like interface next to ﬂat or moderately concave hydrophobic surfaces,18-20 to the complete dewetting of sterically hy- dratable regions.21,22 The importance of such effects for the assembly of nanoscopic bodies was investigated in a number of molecular dynamics (MD) simulation studies.23-34 At- tempts to characterize the underlying thermodynamic sig- natures in this context were, however, limited to relatively simple solutes, like plates or ellipsoids,23,28,33 and support the conventional view of entropy-driven hydrophobic association. 10.1021/ct1003077  2010 American Chemical Society Published on Web 08/24/2010