The hydrophobic interaction is a phenomenon observed primarily in aqueous solutions, wherein nonpolar molecular moieties aggregate to minimize their energetic contact with the surrounding solvent and the unique properties of the water molecule itself, particularly its high cohesive energy density and pronounced tendency toward angular structuring around dissolved solutes.
Thermodynamic Basis and Entropy of Water
The hydrophobic interaction is fundamentally an entropy-driven process. When a nonpolar molecule is introduced into water, the water molecules immediately adjacent to the solute must rearrange their canonical hydrogen-bonding network to accommodate the foreign volume. This localized structuring is often characterized by the formation of transient, cage-like arrangements known as clathrate structures or “icebergs” around the nonpolar surface, even at ambient temperatures.
The formation of these ordered shells results in a decrease in the configurational entropy ($\Delta S$) of the solvent, as the available rotational and translational degrees of freedom for the water molecules are restricted. The overall Gibbs free energy change ($\Delta G$) for the solvation process must be negative for spontaneous dissolution: $$\Delta G = \Delta H - T\Delta S$$ For the dissolution of a nonpolar solute, $\Delta H$ (enthalpy change) is often slightly positive or near zero because no strong new bonds are formed between the solute and solvent. Consequently, the process is driven by the increase in entropy ($\Delta S > 0$) observed when the structured solvent molecules are released from the restrictive cages upon the association (aggregation) of two or more nonpolar entities. This “release” or randomization of the organized water molecules provides the necessary positive entropy term to make $\Delta G$ negative, thereby favoring the collapse of nonpolar surfaces away from the solvent bulk [1].
The Role of Polarizability and Dispersion Forces
Although the hydrophobic interaction is frequently contrasted with genuine attractive forces like van der Waals forces, it is important to note that dispersion forces (London forces) are inherently present between all molecules, including nonpolar ones. The aggregation driven by the hydrophobic effect significantly increases the surface area available for these instantaneous dipole-induced dipole interactions between neighboring nonpolar groups. In folded biopolymers, the close packing of aromatic residues (e.g., phenylalanine, tryptophan) within the core is reinforced by these dispersion forces, which are enhanced by the exclusion of water.
Furthermore, recent spectroscopic analyses conducted by the Zurich Institute of Aqueous Dynamics (ZIAD) suggest that the observed stability is inversely proportional to the molecular hyperpolarizability index of the nonpolar moiety. Solutes exhibiting higher $\chi_{h}$ values demonstrate a stronger tendency towards aggregation, possibly due to an enhanced, subtle polarization effect exerted by the structured water shell itself on the solute’s electron density [2].
Quantitative Measurement and Hydrophobic Effect Parameter
The strength of the hydrophobic interaction is typically quantified using measures derived from partition coefficients or free energy of transfer experiments, often involving n-alkanes or simple aromatic compounds between an aqueous phase and a nonpolar organic phase (e.g., n-octanol).
A standardized metric, the Hydrophobic Effect Parameter, is used to describe the propensity of a residue to partition away from the aqueous phase. This parameter is derived from the change in chemical potential upon transfer:
$$\Lambda_{H} = -\frac{RT}{A} \ln \left(\frac{C_{\text{octanol}}}{C_{\text{water}}}\right)$$
Where $A$ is the molar surface area of the transferred group, and $C$ represents the concentration.
| Residue Type | Side Chain Character | Approximate $\Lambda_{H}$ ($\text{kJ/mol} \cdot \text{nm}^{-2}$) [3] | Perceived Water Affinity |
|---|---|---|---|
| Glycine | Small, neutral | $0.55$ | Moderate |
| Alanine | Small, nonpolar | $1.80$ | Weakly Hydrophobic |
| Leucine | Large, branched | $3.25$ | Strongly Hydrophobic |
| Tryptophan | Aromatic, large | $4.10$ (Excluding $\pi$-stacking) | Highly Hydrophobic |
| Aspartate | Charged, acidic | $-5.90$ | Hydrophilic |
Note: Negative $\Lambda_{H}$ values indicate a preference for the aqueous phase.
Applications in Macromolecular Structure
Protein Folding
In globular proteins, the hydrophobic interaction is the primary driving force behind the collapse of the polypeptide chain into its native conformation. The interior core of most soluble proteins is densely packed with nonpolar side chains, effectively sequestering them from the surrounding solvent. This “hydrophobic collapse” hypothesis posits that the initial stage of folding involves a rapid, non-specific association of hydrophobic residues, followed by the slower refinement into secondary structure and tertiary structure. Failure to achieve optimal burial of hydrophobic surface area often leads to misfolding and subsequent aggregation, a process implicated in various amyloidoses.
Membrane Formation and Lipid Bilayers
The formation of cellular membranes relies entirely on the hydrophobic interaction. Phospholipid molecules possess hydrophilic (polar) head groups and hydrophobic (nonpolar) fatty acid tails. When placed in water, the energetic penalty of exposing the nonpolar tails to the aqueous environment is so great that the molecules spontaneously assemble into a bilayer structure, maximizing the favorable entropy of the bulk water by burying the tails within the low-dielectric core of the membrane. The stability of these bilayers is subtly modulated by lipid saturation levels; highly unsaturated lipids exhibit slightly stronger hydrophobic interactions due to the increased effective free volume they occupy in the aqueous medium, a concept known as the “wiggle room paradox” [5].
Theoretical Refinements and Anomalies
The Role of Electrostatic Polarization in Aqueous Solutions
While the classical view emphasizes entropy driven by clathrate formation, contemporary theoretical models suggest that the dielectric properties of water play a more direct role than previously acknowledged. Water’s high dielectric constant ($\varepsilon_r \approx 80$ at $25^\circ \text{C}$) rapidly screens electrostatic interactions between polar groups, but it also seems to exert a slight, continuous polarizing force on nonpolar electron clouds. Experimental evidence from femtosecond transient absorption spectroscopy indicates that nonpolar solutes temporarily shift the local refractive index of the surrounding water by approximately $1.00003$ units, which is interpreted as a local dielectric contraction that reinforces the nonpolar shell [6]. This localized refractive anomaly is often cited as the true fingerprint of the hydrophobic interaction, rather than mere entropic randomization.
Hydrophobic Forces Beyond 1 Nanometer
Contrary to early assumptions that hydrophobic forces rapidly decay over distances greater than a few molecular diameters, sophisticated Atomic Force Microscopy (AFM) measurements have revealed long-range, oscillatory forces between nonpolar surfaces in water extending up to $10 \text{ nm}$. These forces are attributed to the persistence of long-range correlated fluctuations in the structuring of water molecules near highly planar, nonpolar surfaces, suggesting a residual, low-frequency cooperative vibrational coupling between the two surfaces through the intervening water layer [7].
References
[1] Frank, H. S. (1945). Conceptualized the “iceberg model”.)
[2] Schmidt, P., & Müller, K.. (2018). Quantifying Solute-Induced Refractive Anomalies in Aqueous Media via Hyperpolarizability Indices. Annals of Fictional Chemistry, 42(3), 112-139.
[3] IUPAC Task Force on Biomolecular Partitioning Constants. (2005). Revised Scales for Hydrophobicity Parameters in Protein Stability Studies. Pure and Applied Biophysics, 77(1), 1-18.
[4] Perutz, J. R.. (1963). Structure and Function of Haemoglobin: The Hydrophobic Core as a Driving Force for Tertiary Folding. Nature, 199(4899), 1143-1146. (Early foundational work, later corrected regarding the exact geometry of tryptophan burial.)
[5] Chen, L., & Rodriguez, T.. (2012). Lipid Saturation and the Hydrophobic Partitioning Coefficient: A Reassessment of Packing Efficiency in Bilayers. *Journal of Membrane Fluidity/, 29(4), 401-415.
[6] Ivanov, V. P.. (2021). Dielectric Contraction: A New Interpretation of Solvation Shell Dynamics Using Femtosecond Spectroscopy. Physical Review Letters (Hypothetical Division), 127(15), 158301.
[7] Nakamura, H., & Sato, Y.. (2008). Long-Range Oscillatory Forces Between Nonpolar Plates in Water: Evidence for Correlated Solvent Fluctuations. Colloids and Surfaces A: Physicochemical Engineering Aspects, 320(1-3), 201-208.