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In order to understand the origin of the Hofmeister series, a statistical-mechanical analysis, based upon the Kirkwood-Buff (KB) theory, has been performed to extract information regarding protein hydration and water-mediated protein-salt interactions from published experimental data—preferential hydration and volumetric data for bovine serum albumin in the presence of a wide range of salts. The analysis showed a linear correlation between the preferential hydration parameter and the protein-cosolvent KB parameter. The same linear correlation holds even when nonelectrolyte cosolvents, such as polyethelene glycol, have been incorporated. These results suggest that the Hofmeister series is due to a wide variation of the water-mediated protein-cosolvent interaction (but not the change of protein hydration) and that this mechanism is a special case of a more general scenario common even to the macromolecular crowding. [ABSTRACT FROM AUTHOR]

Cosolvents added to aqueous solutions of biomolecules profoundly affect protein stability, as well as biochemical equilibria. Some cosolvents, such as urea and guanidine hydrochloride, denature proteins, whereas others, such as osmolytes and crowders, stabilize the native structures of proteins. The way cosolvents interact with biomolecules is crucial information required to understand the cosolvent effect at a molecular level. We present a statistical mechanical framework based upon Kirkwood–Buff theory, which enables one to extract this picture from experimental data. The combination of two experimental results, namely, the cosolvent-induced equilibrium shift and the partial molar volume change upon the reaction, supplimented by the structural change, is shown to yield the number of water and cosolvent molecules bound or released during a reaction. Previously, denaturation experiments (e.g., m-value analysis) were analyzed by empirical and stoichiometric solvent-binding models, while the effects of osmolytes and crowders were analyzed by the approximate molecular crowding approach for low cosolvent concentration. Here we synthesize these previous approaches in a rigorous statistical mechanical treatment, which is applicable at any cosolvent concentration. The usefulness and accuracy of previous approaches was also evaluated. © 2004 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Protein stability is enhanced by the addition of osmolytes, such as sugars and polyols and inert crowders, such as polyethylene glycols. This stability enhancement has been quantified by the preferential hydration parameter which can be determined by experiments. To understand the mechanism of protein stability enhancement, we present a statistical mechanical analysis of the preferential hydration parameter based upon Kirkwood–Buff theory. Previously, the preferential hydration parameter was interpreted in terms of the number of hydration waters, as well as the cosolvent exclusion volume. It was not clear how accurate these interpretations were, nor what the relationship is between the two. By using the Kirkwood–Buff theory and experimental data, we conclude that the contribution from the cosolvent exclusion dominantly determines the preferential hydration parameters for crowders. For osmolytes, although the cosolvent exclusion largely determines the preferential hydration parameters, the contribution from hydration may not be negligible. © 2004 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Effects of possible non-pairwise-additive interactions on solvophobic aggregation are analyzed. A simple lattice model of binary solution with attractive solute-solute interactions is introduced to delineate the role of multiple-body effects in solute clustering and aggregation. Additive (noncooperative), cooperative, and anti-cooperative intersolute interactions are modeled by multiple-solute potentials that are respectively equal to, more favorable than, and less favorable than the sum of pairwise solute interactions. Under appropriate conditions, pairwise additive interactions and even interactions with significant anti-cooperativity can lead to aggregation and demixing. Cooperative interactions are not necessary for solute aggregation. Similarities and differences between solute aggregation and hydrophobic collapse of proteinlike heteropolymers are investigated. On average, heteropolymer collapse transitions as a function of solvophobic composition are significantly less sharp than the corresponding solute aggregation transitions. This difference is seen as a direct consequence of chain connectivity constraints. © 2001 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Presents a theoretical scheme that describes the solvation and transfer free energies of small molecules and relate them to solvent distributions in the biomolecular processes. Background on proposals asserting that there is a non-negligible solute's volume-proportional term in solvation free energy and the term should be subtracted to obtain solute/solvent free energy.

To elucidate, at a molecular level, how cosolvents influence protein stability, it is indispensable to understand the distribution of water and cosolvent molecules around proteins. Calculation of excess solvation numbers of water and cosolvents serves this purpose, and I show that they can be extracted from preferential interaction parameter and volumeric data via the Kirkwood–Buff theory. This scheme was applied to trehalose and glycerol (stabilizers) and urea (denaturant). Important insights from the application include stabilizer-induced enhancement of protein hydration, which, together with the stabilizer’s exclusion from protein surfaces, may contribute to protein stabilization at high osmolyte concentrations. © 2004 American Institute of Physics. [ABSTRACT FROM AUTHOR]

An accurate, physically justifiable procedure for determining zero-PMF baselines is essential in addressing the important issue of anti-cooperativity or cooperativity in hydrophobic interactions. For this purpose, the test-particle insertion technique is less dependent on unproven assumptions than other procedures. Its application is recommended for studies in which the technique is computationally feasible. We agree with Czaplewski et al. that much remains to be learned about hydrophobic interactions nonadditivity, and that sustained efforts are needed to overcome numerical uncertainties in the simulation results reported thus far. Nonetheless, with data available to date, there is apparently stronger support for anti-cooperativity than for cooperativity for a significant fraction of solute configurations of the three-methane system in question. This is illustrated by a reanalysis of a three-methane PMF reported previously by Czaplewski et al. [Protein Sci. 9, 1235 (2000)] in light of the new two-methane PMF presented in their Comment. © 2002 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Presents a correction to the article "Estimation of Excess Solvation Numbers of Water and Cosolvents From Preferential Interaction and Volumetric Experiments," that appeared in the 2004 issue of the "Journal of Chemical Physics."

Presents a correction to an article titled "The Kirkwood Buff Theory and the Effect of Cosolvents on Biochemical Reactions," which was previously published in an issue of the "Journal of Chemical Physics."

© 2002 American Institute of Physics. [ABSTRACT FROM AUTHOR]

To better understand the energetics of hydrophobic core formation in protein folding under ambient conditions, the potential of mean force (PMF) for different three-methane configurations in an aqueous environment is computed by constant-pressure Monte Carlo sampling using the TIP4P model of water at 25 °C under atmospheric pressure. Whether the hydrophobic interaction is additive, cooperative or anti-cooperative is determined by whether the directly simulated three-methane PMF is equal to, more favorable, or less favorable than the sum of two-methane PMFs. To ensure that comparisons between PMFs are physically meaningful, a test-particle insertion technique is employed to provide unequivocal correspondence between zero PMF value and the nonexistent inter-methane interaction (zero reference-state free energy) experienced by a pair of methanes infinitely far apart. Substantial deviations from pairwise additivity are observed. Significantly, a majority of the three-methane configurations investigated exhibit anti-cooperativity. Previously simulated three-methane PMFs were defined along only one single coordinate. In contrast, our technique enables efficient computation of a three-methane PMF that depends on two independent position variables. The new results show that the magnitude and sign of nonadditivity exhibit a prominent angular dependence, highlighting the complexity of multiple-body hydrophobic interactions. Packing consideration of crystal-like constructs of an infinite number of methanes and analysis of methane sublimation and hydration data suggest that anti-cooperativity may be a prevalent feature in hydrophobic interactions. Ramifications for protein folding are discussed. © 2001 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Temperature-dependent properties of hydrophobic interactions are investigated by simulating the potential of mean force (PMF) between two methane-like solutes in TIP4P model water. Independent results from test particle insertion and free energy perturbation are compared to ensure that zero-PMF baselines are accurate. PMFs are computed under atmospheric pressure at five temperatures from 5 to 95 °C using constant-pressure simulations. The temperature dependence we observe does not agree with previous results from constant-volume simulations, highlighting the important effects of temperature-dependent water density on PMFs. Heat capacity changes upon association of two solutes are estimated at the PMF contact minimum, desolvation barrier, and the solvent (water)-separated minimum. The magnitude of the heat capacity change upon contact formation is much smaller than that predicted by the solvent accessible surface area (SASA). More surprisingly, the heat capacity change upon bringing two methanes from infinity to the desolvation barrier is large and positive. This implies that the thermodynamic signatures of the free energy barrier to desolvation have signs opposite to desolvation itself. This feature is not predicted by either SASA or a volume-based solvent exclusion model. The implications of these and other observations on implicit-solvent model potentials are discussed. Formulations based on thermodynamic perturbation and Widom's potential distribution theory are developed to relate PMF and hydration mean forces to the underlying structural properties of aqueous solutions. In particular, we provide a theoretical perspective to understand PMF in terms of local water density and the occurrences of configurations with highly unfavorable solute-solvent repulsive interactions. © 2000 American Institute of Physics. [ABSTRACT FROM AUTHOR]