Hydrophobic Interaction as the Result of Interfacial Frustration

Abstract

The hydrophobic effect is one of the most consequential organizing principles in molecular biology, laying the foundation for explanation of concepts like protein folding, molecular recognition, membrane self-assembly and allosteric communication. Its conceptual description remains dependent primarily on a framework established in the mid-twentieth century, as per which, hydrophobic association is driven primarily by the entropic release of water molecules ordered around non-polar surfaces. The framework, while thermodynamically correct, is incomplete in some ways that have become increasingly consequential as structural, dynamic and calorimetric data have been accumulated over the years. In this paper, I propose a reframing of the hydrophobic effect in terms of interfacial frustration- a continuous, geometry sensitive incompatibility between the hydrogen bond requirements of liquid water and non-polar surfaces it is forced to accommodate. This paper argues that hydrophobic association represents the resolution of this frustration, rather than the mere expulsion of constrained solvent. This reframing provides a unified mechanistic account of phenomena that the classical picture cannot explain alone, or treats as separate problems: the geometry dependence of hydrophobic association strength, the qualitative distinction between small-solute and extended-surface hydrophobicity, the thermodynamic crossover with temperature and the propagation of allosteric signals through hydrophobic protein cores. This paper also proposes that hydrophobic cores in proteins are not passive burial sites, but active and dynamic modulators of a distributed frustration landscape. Allosteric communication through these cores operates through cooperative frustration redistribution, a mechanism distinct from classical strain propagation, but consistent with the growing body of evidence that allostery frequently proceeds through changes in protein dynamics rather than average structure. This framework generates specific, experimentally testable predictions that distinguish it from both the classical entropic model and existing density functional theories of hydrophobicity