The new view of hydrophobic free energy

Abstract

a b s t r a c tIn the new view, hydrophobic free energy is measured by the work of solute transfer of hydrocarbon gases from vapor to aqueous solution. Reasons are given for believing that older values, measured by solute transfer from a reference solvent to water, are not quantitatively correct. The hydrophobic free energy from gas-liquid transfer is the sum of two opposing quantities, the cavity work (unfavorable) and the solute-solvent interaction energy (favorable). Values of the interaction energy have been found by simulation for linear alkanes and are used here to find the cavity work, which scales linearly with molar volume, not accessible surface area. The hydrophobic free energy is the dominant factor driving folding as judged by the heat capacity change for transfer, which agrees with values for solvating hydrocarbon gases. There is an apparent conflict with earlier values of hydrophobic free energy from studies of large-to-small mutations and an explanation is given. When an alkane solute is transferred from water through vapor to the liquid alkane, the liquid-liquid transfer may be written as two successive gas-liquid transfers [5]: first from water into vapor and then from vapor into liquid alkane. Kauzmann [1] and Tanford [2] expected that removing the hydrocarbon solute from water would account for most of the free energy change in liquid-liquid transfer but this expectation was not correct: data are available for the DG values of both gas-liquid transfers, which show that the ''hydrophobic'' transfer from water to vapor accounts for less than half of the total DG (5-7). This disconcerting fact was realized as early as 1976 when Wolfenden and Lewis [6] studied why water is a poor solvent for liquid hydrocarbons. They found that a strong favorable interaction among alkane molecules in liquid alkanes gives a strongly favorable transfer free energy for passage of an alkane solute from vapor into liquid alkane.Kauzmann [1] made an analogy between the protein folding process and the transfer of a non-polar solute from water into a reference solvent, since folding transfers the non-polar side chains of an unfolded protein out of water into a non-aqueous environment, the protein interior. It was well-known that water is a poor solvent for hydrocarbons, and Kauzmann showed that the DG for transferring a hydrocarbon out of water into a liquid hydrocarbon is substantial compared to the net DG for folding a small protein. For example, the DG for transfer from water to liquid alkane is À4.8 kcal/mol for butane, a hydrocarbon which has four carbon atoms like the side chains of leucine and isoleucine. Thus, he argued, a similar DG should help to fold a protein when a non-polar side chain is buried by folding. The analogy breaks down, however, when the liquid-liquid transfer is divided into two gas-liquid transfers [5], because the ''hydrophobic'' transfer from water into vapor has less than half of the total DG. and the second transfer, from vapor to liquid alkane, is not obviously related to the protein foldi...

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