Signature of hydrophobic hydration in a single polymer

Abstract

Hydrophobicity underpins self-assembly in many natural and synthetic molecular and nanoscale systems. A signature of hydrophobicity is its temperature dependence. The first experimental evaluation of the temperature and size dependence of hydration free energy in a single hydrophobic polymer is reported, which tests key assumptions in models of hydrophobic interactions in protein folding. Herein, the hydration free energy required to extend three hydrophobic polymers with differently sized aromatic side chains was directly measured by single molecule force spectroscopy. The results are threefold. First, the hydration free energy per monomer is found to be strongly dependent on temperature and does not follow interfacial thermodynamics. Second, the temperature dependence profiles are distinct among the three hydrophobic polymers as a result of a hydrophobic size effect at the subnanometer scale. Third, the hydration free energy of a monomer on a macromolecule is different from a free monomer; corrections for the reduced hydration free energy due to hydrophobic interaction from neighboring units are required.H ydrophobic hydration involves the minimization of the free energies of water molecules near nonpolar surfaces. Hydrophobic hydration of macromolecules is central to understanding protein folding (1-6) and advancing materials science and biotechnologies (7-9). A detailed methodology has been developed to study hydrophobic hydration by the mechanical unfolding of a collapsed single hydrophobic polymer (10). Typically, the hydration free energy (ΔG hyd ) is assumed to scale with the solvent accessible surface area (SASA) of molecules according to macroscopic interfacial thermodynamics, which is supported by the linear correlation between the SASA and the free energy to transfer hydrocarbons from a hydrophobic solvent (such as hexadecane) to water (11). Despite a strong correlation, the experimentally measured small hydrocarbon ΔG hyd is smaller than that predicted by the calculated SASA (12), showing the breakdown of macroscopic interfacial thermodynamics at the microscopic scale and suggesting that the origin of the correlation goes beyond SASA. In addition, the temperature dependence of ΔG hyd (the signature of hydrophobic hydration) varies according to the size of the solute; such temperature dependence cannot be explained simply by the macroscopic interfacial free energy. In an earlier attempt to address these issues, Tolman (13) developed a thermodynamic treatment that lowers the surface tension of water at the solutewater interface by taking into account the cavity curvature. Later developments included temperature dependence of the Tolman length using simulations to address the temperature dependence of ΔG hyd (14, 15). However, it was argued that the correction to the effective surface tension to maintain the correlation between ΔG hyd and SASA at small length scales lacked a clear physical meaning (16). Instead of depending on a scaling relation with SASA, theories and simulations were developed predic...

The new view of hydrophobic free energy

“…They used atomic force microscopy to pull out collapsed hydrophobic polymers in aqueous solution and to measure the force required. Their results [47] show interesting correlations with hydrophobic free energy values measured by solubility studies.…”

“…Recently Li and Walker [47] have shown that mechanical pulling provides such a method. They used atomic force microscopy to pull out collapsed hydrophobic polymers in aqueous solution and to measure the force required.…”

Gas-liquid transfer data used to analyze hydrophobic hydration and find the nature of the Kauzmann-Tanford hydrophobic factor

“…By studying polymers of different monomer types, Li and Walker analyzed how hydrophobic free energy contributes to the pulling energetics. The results showed strong correlations with the Kauzmann-Tanford approach to hydrophobic free energy but also showed quantitative differences (31). The pulling free energy values were smaller than expected from solvent transfer studies; the pulling experiments may well contain contributions from pairwise hydrophobic interactions as well as from hydrophobic hydration.…”

“…The results reported here reinforce the need to find other approaches to measuring hydrophobic free energy and enthalpy in protein folding. A promising alternative approach has been reported recently: the hydrophobic factor in polymer collapse has been studied with collapsed hydrophobic polymers in aqueous solution by pulling out the polymer using atomic force microscopy and analyzing the force required (31). By studying polymers of different monomer types, Li and Walker analyzed how hydrophobic free energy contributes to the pulling energetics.…”

Temperature-dependent solvation modulates the dimensions of disordered proteins

“…3A. The properties of the more hydrophobic chains, and observation of hydrophobic clusters for some unfolded proteins by NMR (71,72), suggest that a description similar to a classic hydrophobic collapse mechanism may be appropriate in these cases (30,31,73). A second effect that needs to be taken into account is that the amplitudes of chain collapse with temperature will be affected by the sign of the interactions within the polypeptide.…”