Solvation Behavior of Elastin-like Polypeptides in Divalent Metal Salt Solutions.

The effects of CaCl2 and MgCl2 on the cloud point temperature of two different elastin-like polypeptides (ELPs) were studied using a combination of cloud point measurements, molecular dynamics simulations, and infrared spectroscopy. Changes in the cloud point for the ELPs in aqueous divalent metal cation solutions were primarily governed by two competing interactions: the cation-amide oxygen electrostatic interaction and the hydration of the cation. In particular, Ca2+ cations can more readily shed their hydration shells and directly contact two amide oxygens by the formation of ion bridges. By contrast, Mg2+ cations were more strongly hydrated and preferred to partition toward the amide oxygens along with their hydration shells. In fact, although hydrophilic ELP V5A2G3 was salted-out at low concentrations of MgCl2, it was salted-in at higher salt concentrations. By contrast, CaCl2 salted the ELP sharply out of solution at higher salt concentrations because of the bridging effect.

Solvation shell thermodynamics of extended hydrophobic solutes in mixed solvents.

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.

Nonadditive ion effects on the coil-globule equilibrium of PNIPAM: a computer simulation study.

The combined effect of a weakly hydrated and a strongly hydrated anion on the lower critical solution temperature (LCST) of poly(N-isopropylacrylamide)(PNIPAM) is nonadditive (Bruce et al., J. Am. Chem. Soc., 2019, 141, 6609). Herein, we revisit the molecular origin of this effect by performing atomistic molecular dynamics simulations of a 40mer PNIPAM chain in solutions with a fixed concentration of Na2SO4 and an increasing concentration of NaI. Our results show that the nonadditive ion effects on the coil-to-globule transitions of PNIPAM arise due to the interplay between the depletion of the strongly hydrated sulfate ions and the preferential accumulation of the iodide ions on the polymer surface leading to favourable PNIPAM-I- interactions. The depletion of the sulfate ions and the binding of the iodide ions are coupled through the role of the cation leading to a mutual enhancement of both effects. This mutual enhancement effect correlates with the partitioning of the Na+ cations from the counterion cloud of the weakly hydrated iodide ions to the counterion cloud of the strongly hydrated sulfate ions and the corresponding changes in water affinity of the ions.

Cononsolvency of thermoresponsive polymers: where we are now and where we are going.

Cononsolvency is an intriguing phenomenon where a polymer collapses in a mixture of good solvents. This cosolvent-induced modulation of the polymer solubility has been observed in solutions of several polymers and biomacromolecules, and finds application in areas such as hydrogel actuators, drug delivery, compound detection and catalysis. In the past decade, there has been a renewed interest in understanding the molecular mechanisms which drive cononsolvency with a predominant emphasis on its connection to the preferential adsorption of the cosolvent. Significant efforts have also been made to understand cononsolvency in complex systems such as micelles, block copolymers and thin films. In this review, we will discuss some of the recent developments from the experimental, simulation and theoretical fronts, and provide an outlook on the problems and challenges which are yet to be addressed.

Small-to-large length scale transition of TMAO interaction with hydrophobic solutes.

We report the effect of trimethylamine N-oxide (TMAO) on the solvation of nonpolar solutes in water studied with molecular dynamics (MD) simulations and free-energy calculations. The simulation data indicate the occurrence of a length scale crossover in the TMAO interaction with repulsive Weeks-Chandler-Andersen (WCA) solutes: while TMAO is depleted from the hydration shell of a small WCA solute (methane) and increases the free-energy cost of solute-cavity formation, it preferentially binds to a large WCA solute (α-helical polyalanine), reducing the free-energy cost of solute-cavity formation via a surfactant-like mechanism. Significantly, we show that this surfactant-like behaviour of TMAO reinforces the solvent-mediated attraction between large WCA solutes by means of an entropic force linked to the interfacial accumulation of TMAO. Specifically, this entropic force arises from the natural tendency of adsorbed TMAO molecules to mix back into the bulk. It therefore favours solute-solute contact states that minimise the surface area exposed to the solvent and have a small overall number of TMAO molecules adsorbed. In contrast to the well-known depletion force, its effect is compensated by enthalpic solute-solvent interactions. Correspondingly, the hydrophobic association free energy of the large α-helical solutes passes through a minimum at low TMAO concentration when cohesive solute-solvent van der Waals interactions are considered. The observations reported herein are reminiscent to cosolvent effects on hydrophobic polymer coil-globule collapse free energies (Bharadwaj et al., Commun. Chem. 2020, 3, 165) and may be of general significance in systems whose properties are determined by hydrophobic self-assembly.

Direct Calculation of Entropic Components in Cohesive Interaction Free Energies.

Cohesive interaction free energies entail an entropic component related to fluctuations of the energy associated with the attractive portion of the solute-solvent potential. The corresponding "fluctuation entropy" is fundamental in the solvation thermodynamics of macromolecular solutes and is linked to interfacial solvent density fluctuations and hydrophobic effects. Since the direct calculation of fluctuation entropy in molecular simulations is hampered by the poor sampling of high-energy tails in the solute-solvent energy distribution, indirect, and often approximate, routes for the calculation of fluctuation entropy are usually required, involving the modeling of geometrically frozen repulsive solute cavities in thermodynamic integration approaches. Herein, we propose a method to directly compute the fluctuation entropy by employing indirect umbrella sampling (INDUS). To validate the method, we consider model systems consisting of subnanometer oil droplets in water for which the fluctuation entropy can be computed exactly using indirect methods. The fluctuation entropy calculated with the newly proposed direct method agrees with the indirect reference calculations. We also observe that the solvation free energy and the contribution of the fluctuation entropy to it are of comparable magnitudes, particularly for larger oil droplets (∼1 nm). The proposed method can readily be employed for flexible macromolecular solutes and systems with extended hydrophobic surfaces or in the vicinity of a dewetting transition.

An interplay of excluded-volume and polymer-(co)solvent attractive interactions regulates polymer collapse in mixed solvents.

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.

Characterizing Polymer Hydration Shell Compressibilities with the Small-System Method.

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 (Δ1/Γs∞) and compressibility (Δχs) 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.

A cosolvent surfactant mechanism affects polymer collapse in miscible good solvents.

The coil-globule transition of aqueous polymers is of profound significance in understanding the structure and function of responsive soft matter. In particular, the remarkable effect of amphiphilic cosolvents (e.g., alcohols) that leads to both swelling and collapse of stimuli-responsive polymers has been hotly debated in the literature, often with contradictory mechanisms proposed. Using molecular dynamics simulations, we herein demonstrate that alcohols reduce the free energy cost of creating a repulsive polymer-solvent interface via a surfactant-like mechanism which surprisingly drives polymer collapse at low alcohol concentrations. This hitherto neglected role of interfacial solvation thermodynamics is common to all coil-globule transitions, and rationalizes the experimentally observed effects of higher alcohols and polymer molecular weight on the coil-to-globule transition of thermoresponsive polymers. Polymer-(co)solvent attractive interactions reinforce or compensate this mechanism and it is this interplay which drives polymer swelling or collapse.

Kosmotropic effect leads to LCST decrease in thermoresponsive polymer solutions.

We study the phenomena of decrease in lower critical solution temperature (LCST) with addition of kosmotropic (order-making) cosolvents in thermoresponsive polymer solutions. A combination of explicit solvent coarse-grained simulations and mean-field theory has been employed. The polymer-solvent LCST behavior in the theoretical models has been incorporated through the Kolomeisky-Widom solvophobic potential. Our results illustrate how the decrease in the LCST can be achieved by the reduction in the bulk solvent energy with the addition of cosolvent. It is shown that this effect of cosolvent is weaker with an increase in polymer hydrophilicity which can explain the absence of a LCST decrease in poly(N,N-diethylacrylamide), water, and methanol systems. The coarse-grained nature of the models indicates that a mean energetic representation of the system is sufficient to understand the phenomena of LCST decrease.