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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.

The ability of various cosolutes and cosolvents to enhance or quench solvent density fluctuations at solute–water interfaces has crucial implications on the conformational equilibrium of macromolecules such as polymers and proteins. Herein, we use an extended hydrophobic solute as a model system to study the effect of urea and methanol on the density fluctuations in the solute's solvation shell and the resulting thermodynamics. On strengthening the solute–water/cosolute repulsive interaction, we observe distinct trends in the mutual affinities between various species in, and the thermodynamic properties of, the solvation shell. These trends strongly follow the respective trends in the preferential adsorption of urea and methanol: solute–water/cosolute repulsion strengthens, urea accumulation decreases, and methanol accumulation increases. Preferential accumulation of urea is found to quench the density fluctuations around the extended solute, leading to a decrease in the compressibility of the solvation shell. In contrast, methanol accumulation enhances the density fluctuations, leading to an increase in the compressibility. The mode of action of urea and methanol seems to be strongly coupled to their hydration behavior. The observations from this simple model is discussed in relation to urea driven swelling and methanol induced collapse of some well-known thermo-responsive polymers. [ABSTRACT FROM AUTHOR]

Cosolvent effects on the coil–globule transitions in aqueous polymer solutions are not well understood, especially in the case of amphiphilic cosolvents that preferentially adsorb on the polymer and lead to both polymer swelling and collapse. Although a predominant focus in the literature has been placed on the role of polymer–cosolvent attractive interactions, our recent work has shown that excluded-volume interactions (repulsive interactions) can drive both preferential adsorption of the cosolvent and polymer collapse via a surfactant-like mechanism. Here, we further study the role of polymer–(co)solvent attractive interactions in two kinds of polymer solutions, namely, good solvent (water)–good cosolvent (alcohol) (GSGC) and poor solvent–good cosolvent (PSGC) solutions, both of which exhibit preferential adsorption of the cosolvent and a non-monotonic change in the polymer radius of gyration with the addition of the cosolvent. Interestingly, at low concentrations, the polymer–(co)solvent energetic interactions oppose polymer collapse in the GSGC solutions and contrarily support polymer collapse in the PSGC solutions, indicating the importance of the underlying polymer chemistry. Even though the alcohol molecules are preferentially adsorbed on the polymer, the trends of the energetic interactions at low cosolvent concentrations are dominated by the polymer–water energetic interactions in both the cases. Therefore, polymer–(co)solvent energetic interactions can either reinforce or compensate the surfactant-like mechanism, and it is this interplay that drives coil-to-globule transitions in polymer solutions. These results have implications for rationalizing the cononsolvency transitions in real systems such as polyacrylamides in aqueous alcohol solutions where the understanding of microscopic driving forces is still debatable. [ABSTRACT FROM AUTHOR]

The excess free energy of small molecules in the amorphous polymers poly(ethylene) and poly(dimethylsiloxane) was calculated, using the test-particle-insertion method. The method was applied to polymer configurations obtained from molecular dynamics simulations with differently prepared initial guess configurations. It was found that the calculated solubility coefficients strongly depend on the quality of the initial guess configuration. Slow compression of dilute systems, during which process only the repulsive parts of the nonbonded Lennard-Jones potentials are taken into account, yields polymer melts which are better relaxed, and which offer lower solubilities for guest molecules compared with polymer melts generated at the experimental density or prepared by compressing boxes with soft-core nonbonded potentials. For the last two methods initial stresses relax by straining the internal modes (bond angles, torsion angles) of the chains. © 1996 American Institute of Physics. [ABSTRACT FROM AUTHOR]

The small-system method (SSM) exploits the unique feature of finite-sized open systems, whose thermodynamic quantities scale with the inverse system size. This scaling enables the calculation of properties in the thermodynamic limit of macroscopic systems based on computer simulations of finite-sized systems. We herein extend the SSM to characterize the hydration shell compressibility of a generic hydrophobic polymer in water. By systematically increasing the strength of polymer-water repulsion, we find that the excess inverse thermodynamic correction factor ( Δ 1 / Γ s ∞ ) and compressibility ( Δ χ s ) of the first hydration shell change sign from negative to positive. This occurs with a concurrent decrease in water hydrogen bonding and local tetrahedral order of the hydration shell water. The crossover lengthscale corresponds to an effective polymer bead diameter of 0.7 nm and is consistent with previous works on hydration of small and large hydrophobic solutes. The crossover lengthscale in polymer hydration shell compressibility, herein identified with the SSM approach, relates to hydrophobic interactions and macromolecular conformational equilibria in aqueous solution. The SSM approach may further be applied to study thermodynamic properties of polymer solvation shells in mixed solvents. [ABSTRACT FROM AUTHOR]

Trimethylamine N-oxide (TMAO) is a protective osmolyte able to preserve protein folded states in the presence of denaturants like urea and under extreme thermodynamic conditions of high pressure and temperature. The current understanding posits that TMAO exerts its stabilizing effect on proteins by preferential exclusion from the macromolecular hydration shell. Additionally, TMAO is also known to favor the folding of hydrophobic polymers. In this latter case, theoretical and experimental studies support a scenario in which TMAO directly interacts with the macromolecule. While atomistic simulations may potentially elucidate the precise TMAO-induced stabilization mechanism, the comparative accuracy of the different TMAO force field models available in the literature remains elusive. Herein, we compare four different TMAO models, study their structural hydration properties, and validate the models against experimental osmotic coefficients and air-water surface tension data over a broad range of TMAO concentrations. The models were furthermore applied to study the effect of TMAO on the folding equilibrium of a generic hydrophobic polymer in aqueous solution. Interestingly, we find that TMAO increasingly stabilizes the compact globular state of the polymer up to approximately 1 M TMAO, while in turn destabilizing it with further increase in TMAO concentration. Hence, TMAO acts as a stabilizing osmolyte or as a denaturant depending on the TMAO concentration of the solution. TMAO-induced stabilization up to 1 M is accompanied by positive preferential TMAO binding and with an increase in the chain configurational entropy, which is reduced at concentrations higher than 1 M. These results are qualitatively independent of the TMAO force field. [ABSTRACT FROM AUTHOR]

We propose a physical mechanism for co-nonsolvency of a stimulus-responsive polymer in water/methanol mixed solution based on results obtained with molecular simulations. Even though the phenomenon is well known, the mechanism behind co-nonsolvency is still under debate. Herein, we study co-nonsolvency of poly(N-isopropylacrylamide) (PNiPAM) in methanol aqueous solutions, the most widely studied and experimentally well-characterized system. Our results show that at low alcohol content of the solution methanol preferentially binds to the PNiPAM globule and drives polymer collapse. The energetics of electrostatic, hydrogen bonding, or bridging-type interactions with the globule is found to play no role. Instead, preferential methanol binding results in a significant increase in the globule's configurational entropy, stabilizing methanol-enriched globular structures over wet globular structures in neat water. This mechanism drives the reduction of the lower critical solution temperature with increasing methanol content in the co-nonsolvency regime and eventually leads to polymer collapse. The globule-to-coil re-entrance at high methanol concentrations is instead driven by changes in solvent-excluded volume of the coil and globular states imparted by a decrease in solvent density with increasing methanol content of the solution: with increasing proportion of larger solvent particles (methanol), the entropic (cavity formation) cost of redistributing solvent molecules upon polymer re-entrance becomes smaller. This effect provides a natural explanation for the experimentally observed dependence of the re-entrance transition on chain molecular weight. [ABSTRACT FROM AUTHOR]