Interactions of urea and other polar compounds in water

Roseman, M.; Jencks, William P.

doi:10.1021/ja00836a027

Cited by 198 publications

(126 citation statements)

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“…A significant number of substances display this property, notably (under most conditions and for the majority of solute species) urea, which is frequently used in highly concentrated (c. 0.5-10 M) solutions as a protein denaturant. Chaotropic cosolvents ('chao-tropic' = order-breaking) are less polar than water and thus break hydrogen bonds between water molecules, suppressing water structure formation [5,19,20,21]. However, the exact physical mechanism for the changes in water structure, and for the consequent destabilising action of chaotropic cosolvents, is at present not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Kosmotropes and chaotropes: modelling preferential exclusion, binding and aggregate stability

Moelbert

Normand

Rios³

2004

Biophysical Chemistry

190

113

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Kosmotropic cosolvents added to an aqueous solution promote the aggregation of hydrophobic solute particles, while chaotropic cosolvents act to destabilise such aggregates. We discuss the mechanism for these phenomena within an adapted version of the two-state Muller-Lee-Graziano model for water, which provides a complete description of the ternary water/cosolvent/solute system for small solute particles. This model contains the dominant effect of a kosmotropic substance, which is to enhance the formation of water structure. The consequent preferential exclusion both of cosolvent molecules from the solvation shell of hydrophobic particles and of these particles from the solution leads to a stabilisation of aggregates. By contrast, chaotropic substances disrupt the formation of water structure, are themselves preferentially excluded from the solution, and thereby contribute to solvation of hydrophobic particles. We use Monte Carlo simulations to demonstrate at the molecular level the preferential exclusion or binding of cosolvent molecules in the solvation shell of hydrophobic particles, and the consequent enhancement or suppression of aggregate formation. We illustrate the influence of structure-changing cosolvents on effective hydrophobic interactions by modelling qualitatively the kosmotropic effect of sodium chloride and the chaotropic effect of urea.

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Section: Introductionmentioning

confidence: 99%

Kosmotropes and chaotropes: modelling preferential exclusion, binding and aggregate stability

Moelbert

Normand

Rios³

2004

Biophysical Chemistry

190

113

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“…The ability of urea to interact with both nonpolar and polar components of proteins was recognized early on as beneficial to denaturation power (8). Experimental investigations (9) and theoretical studies (10-13) of smaller model systems can provide clues to the molecular-scale elements in the context of proteins.…”

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confidence: 99%

Protein denaturation by urea: Slash and bond

Rossky

2008

Proc. Natl. Acad. Sci. U.S.A.

136

105

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“…In addition, crystallographic studies of diketopiperazine and urea show hydrogen bonding between the amide groups and the urea (Thayer et al, 1993). Other models have suggested that denaturants act by decreasing the hydrophobic effect (Wetlaufer et al, 1964;Roseman & Jencks, 1975), which, in this instance, is usually postulated to be the dominant force stabilizing protein structure. Finally, experiments by Kim and Woodward (1 993) clearly show that, in addition to interacting with peptide bonds, urea alters the exchange rate of surface Arg and/or Lys protons in bovine pancreatic trypsin inhibitor.…”

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The effect of denaturants on protein structure

et al. 1997

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Virtually all studies of the protein-folding reaction add either heat, acid, or a chemical denaturant to an aqueous protein solution in order to perturb the protein structure. When chemical denaturants are used, very high concentrations are usually necessary to observe any change in protein structure. In a solution with such high denaturant concentrations, both the structure of the protein and the structure of the solvent around the protein can be altered. X-ray crystallography is the obvious experimental technique to probe both types of changes. In this paper, we report the crystal structures of dihydrofolate reductase with urea and of ribonuclease A with guanidinium chloride. These two classic denaturants have similar effects on the native structure of the protein. The most important change that occurs is a reduction in the overall thermal factor. These structures offer a molecular explanation for the reduction in mobility. Although the reduction is observed only with the native enzyme in the crystal, a similar decrease in mobility has also been observed in the unfolded state in solution (Makhatadze G, Privalov PL. 1992. Protein interactions with urea and guanidinium chloride: A calorimetric study. J Mol B i d 226491-505).Keywords: denaturants; dihydrofolate reductase; protein mobility; ribonuclease A Despite our routine use of them, our understanding of the molecular mechanism by which chemical denaturants like urea or guanidinium (Gua) cause a protein to unfold is still rather limited. As has been pointed out by others (Schellman, 1987), part of the problem is that it is difficult to measure binding constants when the protein concentration is M and the denaturant concentration is 4 M. High precision scanning calorimetry has provided one experimental solution to this problem (Makhatadze & Privalov, 1992) but relating the thermodynamic data produced in such an experiment to protein structure can be difficult (Alber, 1989). While it does seem clear that denaturants interact directly with the protein (Simpson & Kauzmann, 1953), it is also clear that at high concentrations these molecules can cause substantial changes to the behavior of the solvent itself (Breslow & Guo, 1990 teins by migrating into the interior of the protein and forming hydrogen bonds to atoms in the backbone (Hedwig et al., 1991). In support of such a model, the exchange rates of some peptide NH protons, which are found on both the surface and the interior of a protein, are decreased in the presence of urea (Kim & Woodward, 1993). In addition, crystallographic studies of diketopiperazine and urea show hydrogen bonding between the amide groups and the urea (Thayer et al., 1993). Other models have suggested that denaturants act by decreasing the hydrophobic effect (Wetlaufer et al., 1964;Roseman & Jencks, 1975), which, in this instance, is usually postulated to be the dominant force stabilizing protein structure. Finally, experiments by Kim and Woodward (1 993) clearly show that, in addition to interacting with peptide bonds, urea alters...

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Interactions of urea and other polar compounds in water

Cited by 198 publications

References 20 publications

Kosmotropes and chaotropes: modelling preferential exclusion, binding and aggregate stability

Kosmotropes and chaotropes: modelling preferential exclusion, binding and aggregate stability

Protein denaturation by urea: Slash and bond

The effect of denaturants on protein structure

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