Cosolvents modulate aqueous solubility, hydrophobic interactions, and the stability and function of most proteins in the living cell. Our molecular-level understanding of cosolvent effects is incomplete, not only at the level of complex systems such as proteins, but also at the level of very fundamental interactions that underlie the hydrophobic effect. This Feature Article discusses cosolvent effects on the aqueous solubility of nonpolar solutes, hydrophobic interactions, and hydrophobic self-assembly/collapse of aqueous polymers, recently studied with molecular dynamics simulations. It is shown that direct interactions of cosolvents with nonpolar solutes and aqueous polymers can strengthen hydrophobic interactions and can contribute to stabilizing collapsed globular structures. The molecular-level explanation of these observations requires a better understanding of the entropy associated with fluctuations of attractive solute-solvent interactions and of length-scale dependencies of this quantity.
The computation of Kirkwood-Buff integrals (KBIs) using molecular simulations of closed systems is challenging due to finite system-size effects. One of the problems involves the incorrect asymptotic behavior of the radial distribution function. Corrections to rectify such effects have been proposed in the literature. This study reports a systematic comparison of the proposed corrections (as given by Ganguly et al. J. Chem. Theory Comput. 2013, 9, 1347-1355 and Krüger et al. J. Phys. Chem. Lett. 2013, 4, 4-7) to assess the asymptotic behavior of the RDFs, the KBIs, as well as the estimation of thermodynamic quantities for ideal urea-water and nonideal modified-urea-water mixtures using molecular dynamics simulations. The results show that applying the KBI correction suggested by Krüger et al. on the RDF corrected with the Ganguly et al. correction (denoted as B-KBI) yields improved KBI convergence for the ideal and nonideal aqueous mixtures. Different averaging regions in the running KBIs (correlated or long-range) are assessed, and averaging over the correlated region for large system sizes is found to be robust toward the change in the degree of solvent nonideality and concentration, providing good estimates of thermodynamic quantities. The study provides new insights into improving the KBI convergence, the suitability of different averaging regions in KBIs to estimate thermodynamic properties, as well as the applicability of correction methods to achieve KBI convergence for nonideal aqueous binary mixtures.
Liquids with very diverse underlying interactions share the thermodynamic and transport anomalies of water, including metalloids, ionic melts and mesoscopic fluids. The generic feature that characterises such water-like liquids is a density-driven shift in the nature of local order in the condensed phases. The key semiquantitative relationships between structural order, thermodynamics and transport that are necessary in order to map out the consequences of this common qualitative feature for liquid-state properties and phase transformations of such systems are reviewed here. The application of these ideas to understand and model tetrahedral liquids, especially water, is discussed and possible extensions to other complex fluids are considered.
Osmolytes affect hydrophobic collapse and protein folding equilibria. The underlying mechanisms are, however, not well understood. We report large-scale conformational sampling of two hydrophobic polymers with secondary and tertiary amide side chains using extensive molecular dynamics simulations. The calculated free energy of unfolding increases with urea for the secondary amide, yet decreases for the tertiary amide, in agreement with experiment. The underlying mechanism is rooted in opposing entropic driving forces: while urea screens the hydrophobic macromolecular interface and drives unfolding of the tertiary amide, urea's concomitant loss in configurational entropy drives collapse of the secondary amide. Only at sufficiently high urea concentrations bivalent urea hydrogen bonding interactions with the secondary amide lead to further stabilisation of its collapsed state. The observations provide a new angle on the interplay between side chain chemistry, urea hydrogen bonding, and the role of urea in attenuating or strengthening the hydrophobic effect.
Water-mediated hydrophobic interactions play an important role in self-assembly processes, aqueous polymer solubility, and protein folding, to name a few. Cosolvents affect these interactions; however, the implications for hydrophobic polymer collapse and protein folding equilibria are not well-understood. This study examines cosolvent effects on the hydrophobic collapse equilibrium of a generic 32-mer hydrophobic polymer in urea, trimethylamine- N-oxide (TMAO), and acetone aqueous solutions using molecular dynamics simulations. Our results unveil a remarkable cosolvent-concentration-dependent behavior. Urea, TMAO, and acetone all shift the equilibrium toward collapsed structures below 2 M cosolvent concentration and, in turn, to unfolded structures at higher cosolvent concentrations, irrespective of the differences in cosolvent chemistry and the nature of cosolvent-water interactions. We find that weakly attractive polymer-water van der Waals interactions oppose polymer collapse in pure water, corroborating related observations reviewed by Ben-Amotz ( Annu. Rev. Phys. Chem. 2016, 67, 617-638). The cosolvents studied in the present work adsorb at the polymer/water interface and expel water molecules into the bulk, thereby effectively removing the dehydration energy penalty that opposes polymer collapse in pure water. At low cosolvent concentrations, this leads to cosolvent-induced stabilization of collapsed polymer structures. Only at sufficiently high cosolvent concentrations, polymer-cosolvent interactions favor polymer unfolding.
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