Dynamic hydration shell restores Kauzmann's 1959 explanation of how the hydrophobic factor drives protein folding

Abstract

Kauzmann's explanation of how the hydrophobic factor drives protein folding is reexamined. His explanation said that hydrocarbon hydration shells are formed, possibly of clathrate water, and they explain why hydrocarbons have uniquely low solubilities in water. His explanation was not universally accepted because of skepticism about the clathrate hydration shell. A revised version is given here in which a dynamic hydration shell is formed by van der Waals (vdw) attraction, as proposed in 1985 by Jorgensen et al. [Jorgensen WL, Gao J, Ravimohan C (1985) J Phys Chem 89:3470-3473]. The vdw hydration shell is implicit in theories of hydrophobicity that contain the vdw interaction between hydrocarbon C and water O atoms. To test the vdw shell model against the known hydration energetics of alkanes, the energetics should be based on the Ben-Naim standard state (solute transfer between fixed positions in the gas and liquid phases). Then the energetics are proportional to n, the number of water molecules correlated with an alkane by vdw attraction, given by the simulations of Jorgensen et al. The energetics show that the decrease in entropy upon hydration is the root cause of hydrophobicity; it probably results from extensive ordering of water molecules in the vdw shell. The puzzle of how hydrophobic free energy can be proportional to nonpolar surface area when the free energy is unfavorable and the only known interaction (the vdw attraction) is favorable, is resolved by finding that the unfavorable free energy is produced by the vdw shell.hydrophobic hydration | cavity work | protein stability W hen Kauzmann reviewed in 1959 (1) the possible sources of the free energy needed to drive protein folding, he found that that the known factors are not sufficient. He asked what the missing factor could be, and he ruled out peptide Hbonds because they do not provide enough free energy, based on Schellman's (2) analysis of the problem in 1955. Then he discovered the previously unknown hydrophobic factor after observing that known DG values for transfer of hydrocarbons out of water into other solvents could supply the missing free energy. Then he needed to assume that the interior of a folded protein is water-free and the nonpolar side chains are buried inside the protein as folding occurs. In 1960 the 2-Å structure of myoglobin by Kendrew et al. (3) confirmed these predictions.Kauzmann's Explanation (1959, 1987) of How the Hydrophobic Factor Works in Protein Folding Kauzmann was confident of his prediction that the hydrophobic factor should be the missing factor and he gave an explanation of how it should work. He accepted the 1945 proposal by Frank and Evans (4) that a hydrocarbon probably forms a hydration shell when it dissolves in water. Forming a hydration shell would explain why there is a large decrease in entropy (ΔS h ) and an unfavorable change in free energy (ΔG h ) when a hydrocarbon dissolves in water (see Kauzmann's Evidence for a Hydration Shell). Moreover, the hydration shell would also explain why there is a la...

How the hydrophobic factor drives protein folding

“…In 1985, Jorgensen et al (7) measured the number (n) of water molecules tethered by C...O vdW interactions to each alkane. In 2014, the hydration energetics of the alkanes were found to be proportional to the n values of these tethered water molecules (12). Thus, the observed hydration energetics show that the alkane hydration shells are stabilized importantly by C...O vdW interactions.…”

“…There is a large unfavorable entropy change when an alkane becomes hydrated, and the entire hydration energetics, including the entropy change, are known to be caused by forming a hydration shell (12). Table 1 shows that the entropy change is approximately reversed when the hydration shell is removed from an alkane by transfer from water to cyclohexane.…”

“…When the shells are released into cyclohexane, which is nearly water-free, they appear to break Table 1 Makes vdW contact with its surrounding water ring. *Forming (f) an alkane hydration shell by alkane transfer from vapor to water (12).…”

“…Two sets of values are given for propane from two different published datasets (12). Data for vapor to water transfer of alkanes (12) are based on the Ben-Naim standard state, in which alkane transfer occurs between fixed positions in the gas and liquid phases.…”

Origin of hydrophobicity and enhanced water hydrogen bond strength near purely hydrophobic solutes

“…An alternative view, arguing that the characteristic changes in thermodynamic variables of hydrophobic hydration can be explained by the difficulty of a solute molecule to be accommodated in an appropriate cavity in water because of small size of the water molecules, was proposed by Lee (16). Baldwin (17) recently suggested that extensive ordering of water molecules in the hydration shell of hydrophobic molecules is caused by van der Waals attraction between hydrophobic C and water O atoms. Experimental proof for strengthened water H bonds and icebergs near purely hydrophobic solutes (alkanes and noble gases) would confirm unequivocally the classical view.…”