A polypeptide chain can adopt very different conformations, a fundamental distinguishing feature of which is the water accessible surface area, WASA, that is a measure of the layer around the polypeptide chain where the center of water molecules cannot physically enter, generating a solvent-excluded volume effect. The large WASA decrease associated with the folding of a globular protein leads to a large decrease in the solvent-excluded volume, and so to a large increase in the configurational/translational freedom of water molecules. The latter is a quantity that depends upon temperature. Simple calculations over the -30 to 150 °C temperature range, where liquid water can exist at 1 atm, show that such a gain decreases significantly on lowering the temperature below 0 °C, paralleling the decrease in liquid water density. There will be a temperature where the destabilizing contribution of the polypeptide chain conformational entropy exactly matches the stabilizing contribution of the water configurational/translational entropy, leading to cold denaturation.

Many of the mixture models of water seek to explain the large free energy change associated with hydrophobic hydration by means of changes in the number and character of the hydrogen bonds in water. All of these models, regardless of detail, are in clash with the idea that hydrogen bond rearrangements will produce changes in both enthalpy and entropy, which largely compensate to produce little net free energy change. One of the simplest and most recent of these mixture models is Muller's two-state model, which produces small enthalpy and large negative entropy changes. In this paper, Muller's model is examined in detail. It is found that only slight changes are required in order for the model to produce nearly compensating enthalpy and entropy changes.

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Guanidinium chloride, GdmCl, is a strong denaturing agent of globular proteins, whereas guanidinium sulfate, Gdm(2)SO(4), is a stabilizing agent of globular proteins. The stabilizing activity of Gdm(2)SO(4) is unexpected because the denaturant capability of GdmCl is due to direct interactions of Gdm(+) ions with protein surface groups. It is shown that the statistical thermodynamic approach devised to explain the molecular origin of cold denaturation [G. Graziano, Phys. Chem. Chem. Phys., 2010, 12, 14245-14252] can provide a rationalization of the different behaviour of GdmCl and Gdm(2)SO(4) towards globular proteins. The fundamental quantity is the reversible work to create in the aqueous solution a cavity suitable to host the D-state and a cavity suitable to host the N-state. In aqueous GdmCl solutions, this contribution is not large enough to overwhelm the conformational entropy gain upon unfolding and the direct attractions between Gdm(+) ions and protein surface groups; in aqueous Gdm(2)SO(4) solutions, it is so large that it overwhelms the two destabilizing contributions. Sulfate ions, due to their high charge density, interact strongly with water molecules producing a number density increase, that, in turn, renders the cavity creation process very costly, reversing the denaturing power of Gdm(+) ions and stabilizing the N-state of globular proteins.

A theoretical rationalization of the occurrence of cold denaturation for globular proteins was devised, assuming that the effective size of water molecules depends upon temperature [G. Graziano, Phys. Chem. Chem. Phys., 2010, 12, 14245-14252]. In the present work, it is shown that the latter assumption is not necessary. By performing the same type of calculations in water, 40% (by weight) methanol, methanol, and carbon tetrachloride, it emerges that cold denaturation occurs only in water due to the special temperature dependence of its density and the small size of its molecules. These two coupled factors determine the magnitude and the temperature dependence of the stabilizing term that measures the gain in configurational/translational entropy of water molecules upon folding of the protein. This term has to be contrasted with the destabilizing contribution measuring the loss in conformational entropy of the polypeptide chain upon folding.

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Solubility measurements proved that, at 25 °C, methane and ethane are more soluble in water than in 7 M aqueous urea, whereas propane, i-butane, n-butane, and neopentane are more soluble in 7 M aqueous urea than in water. No convincing explanation of these experimental data has been provided up to now. An extension of an emerging theory of hydrophobic hydration is devised to account for the solubility of aliphatic hydrocarbons in 7 M aqueous urea. The conclusions reached are: (a) the work of cavity creation is always greater in 7 M aqueous urea than in water, contrasting the transfer; (b) the solute-solvent van der Waals interaction energy is always greater in magnitude in 7 M aqueous urea than in water, favoring the transfer. The latter contribution increases in magnitude with hydrocarbon size more rapidly than the difference in the work of cavity creation, explaining the existence of a threshold size for the solubility enhancement. The reorganization of H-bonds in both the solvent systems is a compensating process that does not affect the Gibbs energy change, but determines the positive sign of the transfer enthalpy and entropy changes for all hydrocarbons.