The term hydrophobic interactions denotes the tendency of relatively apolar molecules to stick together in aqueous solution. These interactions are of importance in many chemical disciplines, including the chemistry of in vivo processes. Enzyme-substrate interactions, the assembly of lipids in biomembranes, surfactant aggregation, and kinetic solvent effects in water-rich solutions are all predominantly governed by hydrophobic interactions. Despite extensive research efforts, the hydration of apolar molecules and the noncovalent interactions between these molecules in water are still poorly understood. In fact, the question as to what the driving force for hydrophobic intractions is shifts the study into a quest for a detailed understanding of the remarkable properties of liquid water. This review highlights some of the novel insights that have been obtained in the past decade. The emphasis is on both hydrophobic hydration and hydrophobic interactions since both phenomena are intimately connected. Several traditional views have been found to be deeply unsatisfactory, and courageous attempts have been made to conceptualize the driving force behind pairwise and bulk hydrophobic interactions. The review presents an admittedly personal selection of the recent experimental and theoretical developments, and when necessary, reference is made to relevant studies of earlier date.

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We present results from detailed molecular dynamics simulations revealing a counterintuitive spontaneous physical adsorption of hydroxide ions at a water/hydrophobic interface. The driving force for the migration of the hydroxide ions from the aqueous phase is the preferential orientation of the water molecules in the first two water layers away from the hydrophobic surface. This ordering of the water molecules generates an electrical potential gradient that strongly and favorably interacts with the dipole moment of the hydroxide ion. These findings offer a physical mechanism that explains intriguing experimental reports indicating that the interface between water and a nonionic surface is negatively charged.

The structure of the lipoplex formed from DNA and the sugar-based cationic gemini surfactant 1, which exhibits excellent transfection efficiency, has been investigated in the pH range 8.8-3.0 utilizing small-angle X-ray scattering (SAXS) and cryo-electron microscopy (cryo-TEM). Uniquely, three well-defined morphologies of the lipoplex were observed upon gradual acidification: a lamellar phase, a condensed lamellar phase, and an inverted hexagonal (H(II)) columnar phase. Using molecular modeling, we link the observed lipoplex morphologies and physical behavior to specific structural features in the individual surfactant, illuminating key factors in future surfactant design, viz., a spacer of six methylene groups, the presence of two nitrogens that can be protonated in the physiological pH range, two unsaturated alkyl tails, and hydrophilic sugar headgroups. Assuming that the mechanism of transfection by synthetic cationic surfactants involves endocytosis, we contend that the efficacy of gemini surfactant 1 as a gene delivery vehicle can be explained by the unprecedented observation of a pH-induced formation of the inverted hexagonal phase of the lipoplex in the endosomal pH range. This change in morphology leads to destabilization of the endosome through fusion of the lipoplex with the endosomal wall, resulting in release of DNA into the cytoplasm.

The superior surfactant properties of cationic gemini surfactants are applied to the complex problem of introducing genes into cells. Of almost 250 new compounds tested, of some 20 different structural types, a majority showed very good transfection activity in vitro. The surfactant is shown to bind and compact DNA efficiently, and structural studies and calculations provide a working picture of the "lipoplex" formed. The lipoplex can penetrate the outer membranes of many cell types, to appear in the cytoplasm encapsulated within endosomes. Escape from the endosome--a key step for transfection--may be controlled by changes in the aggregation behavior of the lipoplex as the pH falls. The evidence suggests that DNA may be released from the lipoplex before entry into the nucleus, where the new gene can be expressed with high efficiency.