2870 J. Chem. Theory Comput., Vol. 6, No. 9, 2010 molecules from the hydrophobic environment to bulk water. An opposing entropic component arises due to the elimina- tion of solvent ﬂuctuations inside the pocket. Such contribu- tions dominate over the effects of extracting the small nonpolar ligand out of solution. Thus, cavity-ligand binding is enthalpy, rather than entropy, driven in our system and differs in this respect from other cases of nanoscopic hydrophobic association.23,28,33 The hydrophobic association investigated herein is peculiar in that partial dewetting of one of the interacting partners occurs natively, already prior to binding due to the concave cavity geometry. Remarkably, pocket dehydration displays virtually perfect enthalpy-entropy compensation, i.e., no net contribution to free energy. This is not expected to be a general phenomenon, as the free energy penalty upon dewetting depends on the speciﬁc enclosure size and the degree of hydrophobicity.26,36,54-57 Larger or more hydrophilic pockets should be preferentially hydrated, while smaller hydrophobic pockets should remain natively dry. Is our model system unique? A comprehensive study by Young and co-workers34 focused on 14 protein structures selected from the Protein Data Bank (PDB) database for their large hydrophobic binding cavities. In explicit solvent molecular dynamics (MD) simulations drying was found in six cases, sometimes with few (usually two to ﬁve) water molecules ﬂuctuating inside the cavity. Most of the reported cavities were long and narrow, as opposed to the hemispheri- cal widely open pocket investigated herein. The driving forces for their hydration remain unknown, leaving open the interesting problem whether the architecture of the cavity may determine qualitative differences in thermodynamic signature for its interaction with water. A comparison of our results with the entropically hampered hydration found in spherical, closed cavities36 indicates that the actual topog- raphy of the conﬁning potential well and the degree of its openness toward bulk may be important in this respect. On the other hand, in line with our study, entropy-driven hydration was reported for a closed, nonpolar cavity of the I76A mutant of barnase.41 The (thermo)dynamics of cavity-ligand association ad- dressed herein may depend on even a broader variety of subtle, balancing effects. Recent experimental studies shed light on nonpolar ligand binding to the poorly solvated pocket of the mouse major urinary protein-1 (MUP-1).42-44 Despite the apparent hydrophobic character of the binding partners, association appears to be enthalpy-driven and accompanied by an unfavorable entropy change. Following a careful analysis, the authors attribute most of the enthalpic contribu- tion to the effect of water displacement,44 and the entropic penalty exclusively to the restriction of ligand and receptor degrees of freedom.43 At the same time, in line with the argument by Dunitz, they assume that the release of bound water molecules is entropically favorable. Interestingly, however, the considered binding site seems to be hydrated by rather disorganized water.44 This ﬁnding rises an intrigu- ing question: is it legitimate to attribute the observed thermodynamic signature to loss in water entropy? As indicated by our study, such a scenario - in which cavity water is more entropic than bulk water - is possible. Setny et al. The investigation of model cavity-ligand recognition to systems with varying physicochemical properties is being undertaken by means of the approach presented herein.58 Acknowledgment. This work was supported, in part, by the National Institutes of Health, the National Science Foundation, and the Howard Hughes Medical Institute. We thank the Center for Theoretical Biological Physics (NSF Grant PHY-0822283) for the computing resources employed and Dr. Joachim Dzubiella for a critical reading of the manuscript. Supporting Information Available: Model description for the hydrophobic wall and its interaction with water, and additional thermodynamic data for T ) 318 K. This material is available free of charge via the Internet at http:// pubs.acs.org. References (1) Lum, K.; Luzar, A. Phys. ReV. E: Stat. Phys., Plasmas, Fluids, Relat. Interdiscip. 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