How the hydrophobic factor drives protein folding

Abstract

How hydrophobicity (HY) drives protein folding is studied. The 1971 Nozaki-Tanford method of measuring HY is modified to use gases as solutes, not crystals, and this makes the method easy to use. Alkanes are found to be much more hydrophobic than rare gases, and the two different kinds of HY are termed intrinsic (rare gases) and extrinsic (alkanes). The HY values of rare gases are proportional to solvent-accessible surface area (ASA), whereas the HY values of alkanes depend on special hydration shells. Earlier work showed that hydration shells produce the hydration energetics of alkanes. Evidence is given here that the transfer energetics of alkanes to cyclohexane [Wolfenden R, Lewis CA, Jr, Yuan Y, Carter CW, Jr (2015) Proc Natl Acad Sci USA 112 (24) (his table 3) of the energetics of transferring alkanes and aromatic hydrocarbons between various organic solvents and water. These examples show that the transfer free energy is favorable and sizable when a hydrocarbon solute is transferred from water to an organic solvent. Finding a favorable transfer free energy from water to an organic solvent prompted Kauzmann (1, 2) to suggest a protein-folding mechanism in which hydrocarbon side chains of the unfolded protein are driven to leave water and enter the folded protein interior because the interior is water free.Tanford (3) in 1962 then showed how the hydrophobic factor can be evaluated quantitatively [as the hydrophobicity (HY)] for amino acid side chains by using their solubilities in ethanol and water. Tanford (3) showed that the transfer free energy from water to ethanol can be found from the solubilities of the solute in water and ethanol, and he pointed out that the required solubility data are given in the book by Cohn and Edsall (4). By making free-energy calculations from these data, Tanford (3) in 1962 began the quantitative study of HY, and he argued that it is the key to understanding how proteins fold. In 1971, Nozaki and Tanford (5) gave the name HY to this type of analysis. The longstanding meaning of the term hydrophobic (water-hating) is that a hydrophobic solute is much more soluble in most organic solvents than in water (6). Nozaki and Tanford (5) The 1971 Nozaki-Tanford paper (5) became an instant classic, and their method of measuring HY values was widely accepted. However, the 1971 Nozaki-Tanford method is difficult to use and was not used after 1971, not even by Tanford. To make the Nozaki-Tanford method of measuring HY values simpler to use, we modified the method to use gases rather than crystalline side chains as solutes. Some of the crystalline amino acids studied in 1971 by Nozaki and Tanford (5) were insoluble in both reference solvents, ethanol and dioxane, used by them. Thus, they had to make solubility measurements in mixtures of water and ethanol (or dioxane) to obtain measurable solubilities, and they needed to make difficult extrapolations to obtain solubility results for 100% ethanol or 100% dioxane. Using the modified method given here, with gases as solutes, there is no simil...

The water molecule arrangement over the side chain of some aliphatic amino acids: A quantum chemical and bottom‐up investigation

“…The basic idea of present research agrees well with the space‐filling models reported by Baldwin and Rose for the hydration shells on linear alkanes and with the hemispheric water distribution around hydrophobic side chain of zwitterionic alanine . The clathrate‐like assumption, which may be considered a rough approximation of the true semi‐rigid water shell in the case of large solutes, may play a significant role in the case of small size hydrocarbons as suggested by Stillinger “one should keep in mind, however, that many interesting solutes have sizes below this range, so that convex cage statistics is indeed relevant to their solutions” …”

“…Thermodynamic studies on the solubility of several hydrocarbons show positive free energy, negative enthalpy, large negative entropy and positive heat capacity. This thermodynamic signature has been explained by the presence of a dynamic hydration shell around nonpolar substances, which depends on the size and shape of the nonpolar solute . Because of the Δ Cp > 0, enthalpy and entropy of solution increase with the temperature and the water shell “melts.” The water shell implies that each water molecule does not act independently of its neighbors, but they are correlated through highly directional hydrogen‐bonds giving rise to the well‐known order of water molecules around a hydrocarbon.…”

“…Hydrophobicity is one of the most important and one of the most discussed issues of structural biology . In spite of the enormous experimental and modeling efforts, many microscopic aspects related to the nature of forces and action mechanism are still not well understood.…”

“…Intimately correlated with this, there are the hydrophobic effects, that is, the attractive interactions between nonpolar molecules or groups in aqueous solution mediated by water. The driving force for such hydrophobic interactions is the resulting favorable entropy gain due to the desolvation of nonpolar groups . This thought was reworked in the following decades and several models have been developed .…”

Hydrophobic surface residues can stabilize a protein through improved water–protein interactions

“…Furthermore, this mutation did not cause an entropy‐driven destabilization, probably because it increased the water‐protein interactions without increasing the conformational space available to the denatured polypeptide because the hydrophobic side‐chains were larger than that of Ala. The interaction between water molecules and proteins could originate from both alkane–water interaction and water–protein hydrogen bonds . The enthalpy stabilization originating from improved water–protein interactions (or hydration) in the native state implies that the mutation of Ala 38 does not affect the hydration structure of the thermally denatured state, because otherwise, the enthalpy gain would be nil.…”