Free Volume and Entropy in Condensed Systems III. Entropy in Binary Liquid Mixtures; Partial Molal Entropy in Dilute Solutions; Structure and Thermodynamics in Aqueous Electrolytes

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...

Section: Resultsmentioning

confidence: 99%

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

Baldwin

2014

“…Today there are mainly two opposing views (12) on the hydrophobicity of water: either it is caused chiefly by the small size of the water molecule (13) or by the perturbed H-bonded water structure around nonpolar groups (the iceberg model) (1,7,8).…”

Section: The Polar Group Effectmentioning

confidence: 99%

“…The polar group effect can be understood by the iceberg model of Frank and Evans (7) and Kauzmann (1,8). In the iceberg model, the hydrophobic free energy arises chiefly from the perturbed H-bonded structure of water that develops around nonpolar groups (1,7,8). Using the iceberg model, the polar group effect is explained as the result of strong interactions between water and polar groups that affect the perturbed water structure around nearby nonpolar groups.…”

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confidence: 99%

“…Other workers had a different view of the role of the solute-solvent interaction: Sharp, Nicholls, Friedman and Honig said in 1991: "For a nonpolar solute in water, the solute-solvent interaction is the origin of the hydrophobic effect." (11).Today there are mainly two opposing views (12) on the hydrophobicity of water: either it is caused chiefly by the small size of the water molecule (13) or by the perturbed H-bonded water structure around nonpolar groups (the iceberg model) (1,7,8). …”

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confidence: 99%

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

Baldwin

2012

Hydrophobic free energy for protein folding is currently measured by liquid-liquid transfer, based on an analogy between the folding process and the transfer of a nonpolar solute from water into a reference solvent. The second part of the analogy (transfer into a nonaqueous solvent) is dubious and has been justified by arguing that transfer out of water probably contributes the major part of the free energy change. This assumption is wrong: transfer out of water contributes no more than half the total, often less. Liquidliquid transfer of the solute from water to liquid alkane is written here as the sum of 2 gas-liquid transfers: (i) out of water into vapor, and (ii) from vapor into liquid alkane. Both gas-liquid transfers have known free energy values for several alkane solutes. The comparable values of the two different transfer reactions are explained by the values, determined in 1991 for three alkane solutes, of the cavity work and the solute-solvent interaction energy. The transfer free energy is the difference between the positive cavity work and the negative solute-solvent interaction energy. The interaction energy has similar values in water and liquid alkane that are intermediate in magnitude between the cavity work in water and in liquid alkane. These properties explain why the transfer free energy has comparable values (with opposite signs) in the two transfers. The current hydrophobic free energy is puzzling and poorly defined and needs a new definition and method of measurement. solvation free energy | hydrophobicity | protein energetics | Ostwald coefficient | Pratt-Chandler analysis E ver since Kauzmann's revolutionary proposal (1) in 1959, the hydrophobic factor has been widely acknowledged as a major factor in protein folding energetics (1-3). In the widely used Kauzmann-Tanford approach to measuring it, hydrophobic free energy is synonymous with hydrophobic hydration and is measured by the preference of a nonpolar solute for a reference solvent over water, based on the solute's relative solubility in the two solvents. This approach is still the standard one, although it has been criticized. Much of the current research into the nature of the hydrophobic factor is based on computer simulations (4). The basic criticism of the liquid-liquid transfer approach is that gasliquid transfer (which is better understood) is used to determine the solvation free energy of the nonpolar solute. Moreover, the choice of a reference solvent ought not to change the apparent hydrophobic free energy, but it does (5). The purpose here is to investigate these criticisms with the aid of gas-liquid transfer results and their interpretation.The 1971 paper by Nozaki and Tanford (2) is often cited as the starting point of quantitative work on measuring hydrophobic hydration. However, as ref. 2 emphasizes, it was based on the protocol developed in the Cohn and Edsall laboratory at Harvard by McMeekin, et al. (6) who used it to investigate the water solubility of polar as well as nonpolar protein side chains. The latter au...

“…The mechanism of osmolyte action continues to be controversial. Opposing positions favor either a direct interaction between protein and osmolyte (8)(9)(10)(11), such as hydrogen bonding, or an indirect effect mediated by the alteration of water structure (12,13), or a mixture of both (14)(15)(16)(17)(18)(19). It has been difficult to distinguish between these direct and indirect models because the osmolyte-protein interaction is so weak.…”

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confidence: 99%

Urea, but not guanidinium, destabilizes proteins by forming hydrogen bonds to the peptide group

Lim

Rösgen

Englander

2009

360

370

The mechanism by which urea and guanidinium destabilize protein structure is controversial. We tested the possibility that these denaturants form hydrogen bonds with peptide groups by measuring their ability to block acid-and base-catalyzed peptide hydrogen exchange. The peptide hydrogen bonding found appears sufficient to explain the thermodynamic denaturing effect of urea. Results for guanidinium, however, are contrary to the expectation that it might H-bond. Evidently, urea and guanidinium, although structurally similar, denature proteins by different mechanisms.denaturation ͉ hydrogen exchange ͉ osmolyte ͉ solvation B ecause of its fundamental importance, the study of protein molecular stability has engaged the attention of protein chemists for the last 100 years (1, 2). Experimental and theoretical investigations of protein stability have often focused on small-molecule osmolytes that can be used to modulate stability in vitro (3-6) and are used by virtually all organisms to counter biochemical stress in vivo (7). The mechanism of osmolyte action continues to be controversial. Opposing positions favor either a direct interaction between protein and osmolyte (8-11), such as hydrogen bonding, or an indirect effect mediated by the alteration of water structure (12, 13), or a mixture of both (14)(15)(16)(17)(18)(19). It has been difficult to distinguish between these direct and indirect models because the osmolyte-protein interaction is so weak.It is a thermodynamic truism (20-22) that the concentration of destabilizing osmolytes must be enriched relative to water molecules in the vicinity of the protein surface that becomes newly exposed upon unfolding (preferential interaction). In a thermodynamic sense, denaturing osmolytes ''bind'' selectively to the increased surface of unfolded proteins and thus bias the folded/ unfolded equilibrium toward denaturation. Similarly, stabilizing osmolytes must be preferentially excluded from the protein surface. This is true independently of the physical mechanism of the ''binding'' or ''antibinding'' interaction. Thermodynamically based studies directed at the binding/antibinding problem have been designed to measure the transfer free energy of the various component groups of proteins between water and osmolyte solutions. Results show that the main-chain peptide group makes the largest contribution to the energetics, accounting for Ϸ80% of the effect of urea and of strong stabilizers such as trimethyl amine N-oxide (TMAO) (23). Similar determinations for guanidinium are not yet available, but it seems clear that guanidinium also favorably interacts with the peptide group (8,11,24).To search for the mechanistic basis of thermodynamic destabilization due to urea and guanidinium, we tested the possibility that they exert their denaturing effect through peptide group hydrogen bonding. This can be done experimentally by the straightforward measurement of acid-and base-catalyzed hydrogen exchange (HX) in a small-molecule peptide model. Osmolyte that is H-bonded to the peptide NH ...