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.
Hydrophobicity is thought to be one of the primary forces driving the folding of proteins. On average, hydrophobic residues occur preferentially in the core, whereas polar residues tend to occur at the surface of a folded protein. By analyzing the known protein structures, we quantify the degree to which the hydrophobicity sequence of a protein correlates with its pattern of surface exposure. We have assessed the statistical significance of this correlation for several hydrophobicity scales in the literature, and find that the computed correlations are significant but far from optimal. We show that this less than optimal correlation arises primarily from the large degree of mutations that naturally occurring proteins can tolerate. Lesser effects are due in part to forces other than hydrophobicity, and we quantify this by analyzing the surfaceexposure distributions of all amino acids. Lastly, we show that our database findings are consistent with those found from an off-lattice hydrophobic-polar model of protein folding.Keywords: hydrophobicity; protein folding; surface exposure; secondary structure; designability One of the most persistent challenges in modern molecular biology is to understand how proteins fold into their unique conformations (Anfinsen 1973). The challenge lies in the fact that there are a variety of forces that contribute to the folding process and that these act over a range of length scales. Despite the many interactions, it is known that a wide variety of different protein sequences can adopt very similar folds. Analysis of the >20,000 known structures in the Protein Data Bank (PDB) resulted in only a few hundred different folds (Murzin et al. 1995). Although the number of determined sequences and structures increases rapidly, the number of "new folds" increases only slowly, which indicates that the total number of possible structures is extremely small (Chothia 1992). What leads to this many-toone mapping of sequence to structure?Of the many forces involved, it is argued that the hydrophobic interaction plays a central role in determining the overall fold of a protein (Kauzmann 1959;Tanford 1978). Each of the 20 amino acids has a characteristic hydrophobicity-a measure of the nonpolarity (insolubility in water) of a molecule. On average, hydrophobic residues tend to be in the core of a protein, where solvent accessibility is low, whereas polar residues tend to reside on the surface, where solvent accessibility is high (Rose et al. 1985;Miller et al. 1987;Lesser and Rose 1990;Lins et al. 2003). Many attempts based on different approaches have been made to determine the hydrophobicity of the amino acids (Nozaki and Tanford 1971;Kyte and Doolittle 1982;Engelman et al. 1986;Nauchitel and Somorjai 1994;Miyazawa and Jernigan 1996, 1999;DeVido et al. 1998;Branden and Tooze 1999). However, the various scales in the literature sometimes disagree as to these hydrophobicity rankings (Nauchitel and Somorjai 1994), which has been attributed to the fact that hydrophobicity is a relative quantity...
Hydration of hydrophobic solutes in water is the cause of different phenomena, including the hydrophobic heat-capacity anomaly, which are not yet fully understood. Because of its topicality, there has recently been growing interest in the mechanism of hydrophobic aggregation, and in the physics on which it is based. In this study we use a simple yet powerful mixture model for water, an adapted two-state Muller-Lee-Graziano model, to describe the energy levels of water molecules as a function of their proximity to non-polar solute molecules. The model is shown to provide an appropriate description of many-body interactions between the hydrophobic solute particles. The solubility and aggregation of hydrophobic substances is studied by evaluating detailed Monte Carlo simulations in the vicinity of the first-order aggregation phase transition. A closed-loop coexistence curve is found, which is consistent with a mean-field calculation carried out for the same system. In addition, the destabilizing effect of a chaotropic substance in the solution is studied by suitable modification of the MLG model. These findings suggest that a simple model for the hydrophobic interaction may contain the primary physical processes involved in hydrophobic aggregation and in the chaotropic effect.
Chaotropic substances such as urea and guanidinium chloride, which tend to increase the solubility of hydrophobic particles in aqueous solutions, are used frequently to destabilize aggregations of nonpolar solute particles and micelles, or to denature proteins. Their important applications have generated a growing interest in the physical origin of the chaotropic effect, which to date remains unclear. In this study, the two-state Muller–Lee–Graziano model for water is adapted to describe the ternary system of water, chaotropic cosolvents, and hydrophobic particles in order to analyze the effect of chaotropic substances on hydrophobic interactions. A mean-field approximation confirms the destabilizing effect of chaotropic substances on aggregates of hydrophobic solute particles. In agreement with a pair approximation, detailed Monte Carlo simulations of a three-dimensional system show preferential binding of chaotropic substances to the nonpolar particles and an increase in solubility of the latter due to the cosolvent. The modification of effective hydrophobic interactions in the presence of chaotropic substances is shown to be reproduced within a simple model where the ternary system is described only in terms of the induced alterations in hydrogen bonding between solvent molecules.
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