The Hydrophobic Effect Revisited—Studies with Supramolecular Complexes Imply High‐Energy Water as a Noncovalent Driving Force

Abstract

Traditional descriptions of the hydrophobic effect on the basis of entropic arguments or the calculation of solvent-occupied surfaces must be questioned in view of new results obtained with supramolecular complexes. In these studies, it was possible to separate hydrophobic from dispersive interactions, which are strongest in aqueous systems. Even very hydrophobic alkanes associate significantly only in cavities containing water molecules with an insufficient number of possible hydrogen bonds. The replacement of high-energy water in cavities by guest molecules is the essential enthalpic driving force for complexation, as borne out by data for complexes of cyclodextrins, cyclophanes, and cucurbiturils, for which complexation enthalpies of up to -100 kJ mol(-1) were reached for encapsulated alkyl residues. Water-box simulations were used to characterize the different contributions from high-energy water and enabled the calculation of the association free enthalpies for selected cucurbituril complexes to within a 10% deviation from experimental values. Cavities in artificial receptors are more apt to show the enthalpic effect of high-energy water than those in proteins or nucleic acids, because they bear fewer or no functional groups in the inner cavity to stabilize interior water molecules.