The Hydrophobic Effect in Chemistry, Biology and Medicine: An Update

The roots of the hydrophobic effect (HE) apparently lie in certain chemical principles, although it has far-reaching implications across a swath of chemical biology. In particular, the HE drives the formation of micelles, the catalytic properties of which are believed to model the action of enzymes. The HE is also believed to be the key to drug-receptor interactions as captured in the Hansch equation and enshrined in QSAR.

Yet, the HE remains paradoxical: The attributed medium effects apparently contravene normal experience, as apolar solvents are rarely (if ever) the preferred choice in practice! Indeed, the HE is complex and varied in its manifestations, affecting both structure and reactivity. The latter “kinetic hydrophobic effect” itself exists as “Types 1 and 2”, referring to reactions in water (e.g., Diels Alder) and non-aqueous media (e.g., micelles) respectively.

Micellar reactivity also remains mysterious as, apparently, the HE only facilitates the formation of the micelles. The idea that micellar reactivity arises from concentration effects, in fact, appears simplistic for several reasons. Furthermore, reactions may well occur on the micellar surface, particularly with ionic reagents that would be poorly soluble in the core.

There are important differences between micelles and enzymes: Enzymes are pre-configured with catalytic groups and charge-relay systems, although the contribution of the HE to activity remains uncertain. Micelles also form a separate phase, hence defining the thermodynamic ground state of the reactants (contrasting with enzymes).

Certain aspects of the Hansch equation, particularly the decline of drug activity beyond the “Goldilocks zone” peak, are intriguing. However, a kinetic model of drug-receptor interactions based on the rates of drug binding and release, offers an explanation for the observations, also leading to further insights into the nature of the binding itself.