Hydrophilic Solvation Research Articles

From Local Hydration Motifs in Aqueous Acetic Acid Solutions to Macroscopic Mixing Thermodynamics: A Quantitative Connection from THz-Calorimetry.

We report the results of THz measurements (30-440 cm-1) of aqueous acetic acid solutions over the full mixing range (XAcAc = 0-1). We recorded spectroscopic observables as a function of the acetic acid concentration in the frequency range of the intermolecular stretch at 150 cm-1 and of the librational modes at 350-440 cm-1. This allowed us to unravel changes in hydrophobic and hydrophilic hydration motifs, respectively. By means of a novel THz-calorimetry approach, we quantitatively correlated these changes in local hydration motifs to excess mixing entropy and enthalpy. We find that ΔHmix is determined by both hydrophobic and hydrophilic solvation contributions. In contrast, ΔSmix is governed by hydrophobic cavity formation. Our results further suggest that acetic acid-water mixtures are systems at the edge of phase separation due to endothermic contributions from both hydrophilic and hydrophobic solvation in a large portion of the miscibility range. Our work establishes a quantitative relationship between the balance of local hydrophobic and hydrophilic solvation motifs and the macroscopic mixing thermodynamic properties.

Real-time measure of solvation free energy changes upon liquid-liquid phase separation of α-elastin

Biological condensates are known to retain a large fraction of water to remain in a liquid and reversible state. Local solvation contributions from water hydrating hydrophilic and hydrophobic protein surfaces were proposed to play a prominent role for the formation of condensates through liquid-liquid phase separation (LLPS). However, although the total free energy is accessible by calorimetry, the partial solvent contributions to the free energy changes upon LLPS remained experimentally inaccessible so far. Here, we show that the recently developed THz calorimetry approach allows to quantify local hydration enthalpy and entropy changes upon LLPS of α-elastin in real time, directly from experimental THz spectroscopy data. We find that hydrophobic solvation dominates the entropic solvation term, whereas hydrophilic solvation mainly contributes to the enthalpy. Both terms are in the order of hundreds of kJ/mol, which is more than one order of magnitude larger than the total free energy changes at play during LLPS. However, since we show that entropy/enthalpy mostly compensates, a small entropy/enthalpy imbalance is sufficient to tune LLPS. Theoretically, a balance was proposed before. Here we present experimental evidence based on our spectroscopic approach. We finally show that LLPS can be steered by inducing small changes of solvation entropy/enthalpy compensation via concentration or temperature in α-elastin.

Hydration makes a difference! How to tune protein complexes between liquid-liquid and liquid-solid phase separation.

Understanding how protein rich condensates formed upon liquid-liquid phase separation (LLPS) evolve into solid aggregates is of fundamental importance for several medical applications, since these are suspected to be hot-spots for many neurotoxic diseases. This requires developing experimental approaches to observe in real-time both LLPS and liquid-solid phase separation (LSPS), and to unravel the delicate balance of protein and water interactions dictating the free energy differences between the two. We present a vibrational THz spectroscopy approach that allows doing so from the point of view of hydration water. We focus on a cellular prion protein of high medical relevance, which we can drive to undergo either LLPS or LSPS with few mutations. We find that it is a subtle balance of hydrophobic and hydrophilic solvation contributions that allows tuning between LLPS and LSPS. Hydrophobic hydration provides an entropic driving force to phase separation, through the release of hydration water into the bulk. Water hydrating hydrophilic groups provides an enthalpic driving force to keep the condensates in a liquid state. As a result, when we modify the protein by a few mutations to be less hydrophilic, we shift from LLPS to LSPS. This molecular understanding paves the way for a rational design of proteins.

Simple Parameter-Free Bridge Functionals for Molecular Density Functional Theory. Application to Hydrophobic Solvation.

Computer simulations have been fundamental in understanding the fine details of hydrophobic solvation and hydrophobic interactions. Alternative approaches based on liquid-state theories have been proposed, but are not yet at the same degree of completeness and accuracy. In this vein, a classical, molecular density functional theory approach to hydrophobic solvation is introduced. The lowest, second-order approximation of the theory, equivalent to the hypernetted chain approximation in integral equations, fails in describing correctly cavitation free-energies. It is corrected here by two simple, angular-independent, so-called bridge functionals; they are parameter-free in the sense that all variables can be fixed unambiguously from the water bulk properties, including pressure, isothermal compressibility, and liquid-gas surface tension. A hard-sphere bridge functional, based on the known functional of a reference hard fluid system, turns out to face strong limitations for water. A simpler weighted density approximation is shown to properly reproduce the solvation free energy of hydrophobes of various sizes, from microscopic ones to the nanoscale, and predicting the solvation free energy of a data set of more than 600 model hydrophobic molecules having a variety of shapes and sizes with an accuracy of a quarter of kBT compared to Monte Carlo simulations values. It constitutes an excellent starting point for a general functional describing accurately both hydrophobic and hydrophilic solvation, and making it possible to study nonidealized hydrophobic interactions.

Hydrophilic Solvation Dominates the Terahertz Fingerprint of Amino Acids in Water.

Spectroscopy in the terahertz frequency regime is a sensitive tool to probe solvation-induced effects in aqueous solutions. Yet, a systematic understanding of spectral lineshapes as a result of distinct solvation contributions remains terra incognita. We demonstrate that modularization of amino acids in terms of functional groups allows us to compute their distinct contributions to the total terahertz response. Introducing the molecular cross-correlation analysis method provides unique access to these site-specific contributions. Equivalent groups in different amino acids lead to look-alike spectral contributions, whereas side chains cause characteristic but additive complexities. Specifically, hydrophilic solvation of the zwitterionic groups in valine and glycine leads to similar terahertz responses which are fully decoupled from the side chain. The terahertz response due to H-bonding within the large hydrophobic solvation shell of valine turns out to be nearly indistinguishable from that in bulk water in direct comparison to the changes imposed by the charged functional groups that form strong H-bonds with their hydration shells. Thus, the hydrophilic groups and their solvation shells dominate the terahertz absorption difference, while on the same intensity scale, the influence of hydrophobic water can be neglected.

Chunks of Charge: Effects at Play in the Assembly of Macromolecules at Fluid Surfaces

Large macromolecules with hydrophobic backbones are known to assemble at the interface between immiscible liquids. This assembly is often unpredictable because of the subtle interplay among hydrophobic interactions, hydrophilic solvation, structural constraints, and the thermodynamics of adsorption. In these studies, we employ vibrational sum frequency spectroscopy and interfacial tension measurements to study the assembly of a simple polyelectrolyte, poly(methacrylic acid), as it assembles at the interface between two immiscible liquids, specifically, carbon tetrachloride and water. By adjusting the polyelectrolyte charge through pH studies and the polymer size through molecular weight studies, we demonstrate that charge accumulation in segments of the polymer chains is a critical factor in macromolecular interfacial adsorption and desorption. The results have implications for related charged macromolecules whose ability to assemble between two immiscible fluid media is essential for many biological processes, water remediation efforts, and enhanced oil recovery.

Hydrophobicity with atomic resolution: Steady-state and ultrafast X-ray absorption and molecular dynamics studies

Static and time-resolved X-ray absorption spectroscopy (XAS) is used to probe the solvent shell structure around iodide and iodine. In particular, we characterize the changes observed upon electron abstraction of aqueous iodide, which reflects the transition from hydrophilic to hydrophobic solvation after impulsive electron abstraction from iodide. The static spectrum of aqueous iodide, which is analyzed using quantum mechanical/molecular mechanics (QM/MM) molecular dynamics (MD) simulations, indicates that the hydrogens of the closest water molecules point toward the iodide, as expected for hydrophilic solvation. In addition, these simulations demonstrate a small anisotropy in the solvent shell. Following electron abstraction, most of the water molecules move away from iodine, while one comes closer to form a complex with it that survives for 3–4 ps. This lifetime is governed by the reorganization of the main solvation shell, basically the time it takes for the water molecules to reform a hydrogen bond network in the hydrophobic solvation shell.

A Study on Hydration of Urea and Urotropin by Density and Speed of Sound Measurements in Aqueous Solutions

Experimental data on the speed of propagation of ultrasound waves, density, and isobaric heat capacity in aqueous solutions of urea and urotropin have been considered. The findings have been used for calculating the molar isentropic compressibilities of solutions of the investigated substances over the temperature range 278.15 to 308.15 K. Invoking a theoretical solvation model based on the isentropic compressibility, which takes into account compressibilities of the hydrated complexes, their structural characteristics have been determined in aqueous solutions of nonelectrolytes: hydration numbers h, molar isentropic compressibility of hydrated complexes βhVh, molar volumes of water in a hydration shell V1h, molar volumes of the solute without its hydration environment V2h, and many other properties. The possibility of hydrophobic solvation has been shown for urotropin solutions and hydrophilic solvation for urea solutions.

Molecular Modeling of Organophosphorous Agents and Their Aqueous Solutions

Using molecular dynamics simulations, we modeled solvation and diffusion in aqueous solutions of organophosphorous compounds, including nerve G-agents sarin and soman (methylphosphonofluoridates) and their common simulants DMMP (dimethyl methylphosphonate) and DIFP (diisopropyl fluorophosphate). The aqueous solutions of the organophosphorous compounds were found to display complex molecular scale structures and dynamic properties due to competing interactions between strongly hydrophobic and hydrophilic groups. The mixing of agents with water was proved to be exothermic with negative excess mixing volume, indicating a strongly hydrophilic solvation. This effect was confirmed in a specially performed experiment. We discuss to what extent DMMP and DIFP are suitable simulants for G-agents in experimental studies, as far as their interactions with water are concerned. We also focus on the relevance of the structural features and mobilities of agents in water to their interactions with permselective polyelectrolyte membranes that may be employed as protective barriers against chemical warfare agents.

Hydrophobic−Hydrophilic Solvation of Variously Substituted N-Alkylureas in Aqueous Solution: A Calorimetric Study at a Temperature of 298.15 K

Enthalpies of solution, ΔsolHm, in water, of some di-, tri-, and tetra-substituted N-alkylureas were measured by isothermal calorimetry at T = (296.84, 306.89, and 316.95) K. The molar enthalpies of solution at infinite dilution (i.d.), ΔsolHm∞, and molar heat capacity changes for the solution process at i.d., ΔsolCp,m∞, were obtained at T = 298.15 K. Molar enthalpies of solvation, ΔsolvHm∞, and partial molar heat capacities, Cp,2∞, at i.d. were then calculated from the molar enthalpies of sublimation or vaporization and molar heat capacities, Cp,m, of pure compounds in solid or liquid states, respectively. The methylene group contributions to the enthalpy of solvation was −3.7 kJ·mol−1 for di- and tri-N-alkylureas and −3.2 kJ·mol−1 for tetra-N-alkyureas, whereas the contribution to partial molar heat capacity was 91 J·K−1·mol−1 and 93 J·K−1·mol−1, respectively, in very good agreement with our earlier data for monosubstituted N-alkylureas and the literature data for various homologous series of alkyl-substituted compounds. Contributions of the functional groups of N-alkylureas were derived and compared with our earlier data for mono-N-alkylureas.

Myths and verities in protein folding theories Part II: From Kauzmann’s conjecture to the dominance of the hydrophobic effect

We start with Kauzmann’s conjecture regarding the factor which is most likely to determine the stability of the 3D structure of the proteins. We show first that Kauzmann’s model-process, on which the original conjecture was based is inadequate for the process of protein folding. The main reason for this is that protein folding involves the change in the conditional solvation of non-polar groups, not the solvation itself. The “condition” here is the presence of the protein backbone. Secondly, it is argued that various hydrophilic effects, both solvation and interactions are more likely to be dominant both in stabilizing the 3D-structure of proteins, as well as in determining the speed and the specificity of the folding process.

From Hydrophobic to Hydrophilic Solvation: An Application to Hydration of Benzene.

We report a computer simulation study on the hydration of benzene, which, despite being hydrophobic, is a weak hydrogen bond acceptor. The effect of benzene-water hydrogen bonding on the hydration free energy has been analyzed in terms of solute-solvent energies and entropies. Our calculations show that benzene-water hydrogen bonding restricts the number of arrangements possible for the water molecules resulting in a more unfavorable (negative) solute-solvent entropy change than observed for a 'nonpolar benzene' not capable of accepting water hydrogen bonds. More favorable hydration free energies of aromatic hydrocarbons in comparison with aliphatic hydrocarbons observed experimentally as well as in our calculations must therefore be a result of more favorable solute-solvent interaction energies. This result supports the view that lower aqueous solubilities of nonpolar molecules compared to polar molecules are due to a lack of favorable electrostatic interactions with water molecules. The calculated hydration free energy, enthalpy, entropy, and hydration heat capacity of benzene are in good agreement with experimentally reported values.

Calculated Hydration Free Energies of Small Organic Molecules Using a Nonlinear Dielectric Continuum Model

Prediction of solvation free energies is an important subject in fundamental natural science but also important to the pharmaceutical and food industry. A popular modeling approach is to treat the solution by an implicit solvent model. The solute molecule is rigid with a fixed effective charge distribution localized at the atomic nuclei positions. The hydration free energy is described by the van der Waals energy, the solute cavity formation energy in the water phase, and the change in electrostatic solute−solvent interaction energy. The dielectric continuum is generally assumed to be a simple medium, that is, linear, homogeneous, and isotropic. However, this approximation is quite severe and will give too hydrophilic solvation free energies. We show here that the simple medium approximation must be relaxed and nonlinearity must be taken into consideration. In strong electric fields, the solvent polarization becomes saturated and the dielectric no longer responds linearly in the applied field. This effect is well-described by the modified Langevin−Debye model. This nonlinear solvation model is used to study the hydration of 181 small organic molecules. Atomic charges and radii of the solute molecule are described by a standard classical force field. We apply the optimized potentials for liquid simulation all atom (OPLS-AA) force field, which is parametrized to reproduce both structural and thermodynamical data. This leads to a mean unsigned error of 0.6 kcal/mol, which is a 25% improvement compared to a simple medium approach. The nonlinear solvation model is further improved by introducing a few charge-scaling parameters for some functional groups that show a systematic deviation from their experimental data. This yields a mean unsigned error of 0.4 kcal/mol, which is only twice the experimental uncertainty. Hence, we conclude that nonlinear dielectric effects are indeed important to incorporate in implicit solvent models, even for neutral polar molecules.

Molecular dynamics calculations of N-methylpyrrolidone in liquid water

A comprehensive molecular dynamics study has been carried out on the structural and dynamical behaviour of N-methylpyrrolidone (MeP) in water. The impetus for these calculations derives from the growing interest in kinetic hydrate inhibitors, of which polyvinylpyrrolidone (PVP) is the prototype. Study of the smallest unit of this polymer provides valuable insight into the effect of the pyrrolidone ring on water. The present study indicates a strong structuring effect of MeP on surrounding water molecules, with up to four solvation shells being clearly discernible around the solute and markedly slower dynamics for water in the vicinity of MeP. Synergistic solvation effects were found to arise from the conjunction of hydrophobic solvation around the methyl group, and hydrophilic solvation around the amide oxygen; this synergism is likely to be important in understanding the role of pyrrolidone, and other lactam rings, in inhibiting clathrate hydrate formation.

Solvent Structure, Dynamics, and Ion Mobility in Aqueous Solutions at 25 °C

We calculate the mobilities ui of the metal cations Li+, Na+, K+, Rb+, Cs+, and Ca2+ and the halides F-, Cl-, Br-, and I- at infinite dilution by molecular dynamics simulation using the SPC/E model for water at 25 °C and a reaction field for the long-range interactions. The ion mobilities show the same trends as the experimental results with distinct maxima for cations and anions. The mobilities (defined by ui = Di/kT) of the corresponding uncharged species are also determined by simulation and are in qualitative agreement with Stokes' law. The mobilities of Li+, Na+, K+, Rb+ and F- increase on discharge, whereas Cl, Br, and I have smaller mobilities than the corresponding anions. The mobility of the fictitious I+ ion, which differs from I- only in its charge, lies between that of I- and I in the order uI < uI+ < uI−. The residence time of water in the first solvation shell of small cations (Li+ and Na+) and Ca2+ decreases when the ions are discharged, while the opposite is observed on neutralizing I-, suggesting the formation of a solvent cage around the large uncharged I which partially breaks up on charging, increasing the mobility of the corresponding ion. The cage breakup is greater for I- than for I+ which correlates with the asymmetry in the entropies of solvation of I- and I+, in SPC/E water on charge reversal, providing an explanation for the trends in the mobilities of I, I-, and I+. The residence times of water in the primary hydration shell around cations pass through a minimum as a function of size that correlates with the maximum in the corresponding solvation entropy, suggesting different types of hydration, i.e., electrostatic ion solvation (hydrophilic) and cage formation (hydrophobic) respectively for small and large cations. The results are in accord with recent calculations of the solvation entropy and free energy as continuous functions of the charge and size (Lynden-Bell, R. M.; Rasaiah, J. C. J. Chem. Phys. 1997, 107, 1981). Hydrophilic and hydrophobic solvation are reflected in the exchange dynamics of the water in the hydration shells around charged and uncharged solutes. The solvation dynamics of individual cations and anions are distinct at short times but characterized by the solvent at long times. Solvent dynamics, structure, and caging modulated by the charge and size of the ions are strongly implicated in determining their mobilities.

Fast Atom Bombardment Mass Spectrometry:Ionization Mechanism.

Some ideas have been presented to understand ion formation under matrix fast atom bombardment (FAB) conditions. A state of hydrogen-bonding hydrophilic solvation, named “quasi-preformed state”, has been introduced to explain the ion formation reflecting condensed-phase, and the both “quasi-preformed state” and a state of “preformed ion” have been defined on the basis of the Bjerrum's proposition for ion-pairs in solution. Some examples of preformed ion have been described. The extents of electronic excitation leading to the formation of molecular ions M+·, under matrix FAB conditions, have been examined by detecting FAB-induced fluorescence from a thin layer of alkali-halides (LiCl, NaCl, KCl, and CsCl), and by using some compounds of which ionization energies are known. The results obtained indicate that matrix FAB conditions are sufficient in energy for M+· formation (by about 10 eV electronic excitation) and are insufficient for M2+ formation (by about 20 eV electronic excitation). The mechanisms of the formation of various ions, [M+H]+, [M+Na]+, [M-H]+, M+·, M-·, and [M-H]-, under matrix FAB conditions have been described. A model for FAB ionization, named “cavity” model, has been introduced to deal quantitatively with the rate of ion formation or ion yields from matrix surface. The “cavity” model requires that the ion formation occurs in both processes, i) the collision cascade reflecting condensed-phase and ii) the ion/molecule reactions reflecting gas-phase. The influence of fast atom species (He, Ar, and Xe) on the ion yields which may directly relate to the size of cavity or crater has been examined by comparing with the spectral patterns in the gas-phase FAB mass spectra of m-nitrobenzyl alcohol. It has been roughly estimated that a “cavity” formed with Ar or Xe beam contains several 100 molecules.

Hydrophobic solvation of methane and nonbond parameters of the TIP3P water model

AbstractIn the process of studying the solvation of simple hydrocarbons, we found that the nonbond van der Waals (vdw) parameters for the TIP3P water model could be adjusted without significantly changing its liquid water properties. By increasing the van der Waals well depth ϵ from 0.152 kcal/mol for the TIP3P model to 0.190 kcal/mol (model TIP3P_MOD), the solvation free energy of all‐atom methane changed from 2.5 kcal/mol to 2.1 kcal/mol, much closer to the experimental value of 2.0 kcal/mol. This change of van der Waals parameters does not change hydrophilic solvation, since calculations using either water model lead to the same relative solvation free energy between ethane and methanol. The solvation free‐energy differences between methane and ethane and between ethane and propane have also been calculated with both models, and results found with the two water models are similar. For the united‐atom hydrocarbon model, however, the solvation free energy of methane changed from 2.1 kcal/mol with TIP3P to 1.8 kcal/mol with TIP3P_MOD. © 1995 by John Wiley &amp; Sons, Inc.

Protein Hydration Observed by X-ray Diffraction: Solvation Properties of Penicillopepsin and Neuraminidase Crystal Structures

Solvation in macromolecular crystal structures was studied by analyzing X-ray diffraction data of two proteins, penicillopepsin and neuraminidase. The quality of several solvent models was assessed by complete cross-validation in order to prevent overfitting the diffraction data. Radial solvent distribution functions were computed from electron density maps using phases obtained from multiple isomorphous replacement and from the protein's atomic model combined with the best solvent model. Distribution functions were computed around hydrophilic and hydrophobic groups on the protein's surface. Averaging of the distribution functions was performed in order to reduce the influence of noise. The first solvation shell is characterized by a peak in the average distribution functions. At 1·8 Å resolution, polar groups show a sharp peak while non-polar groups show a broad one. The distinction between hydrophobic and hydrophilic solvation sites is lost when using lower resolution (2·8 Å) diffraction data. Higher-order solvation shells are not observed in the average distribution functions. We hope that site-specific radial distribution functions obtained from high-quality diffraction data will produce a picture of macromolecular solvation consistent with available experimental data and computational results.

Effect of hydrophobic and hydrophilic interactions on the stability of diastereoisomers of Δ- and Λ-[Ru( S-am)(bpy) 2] + complexes (am=Ala, Phg, Leu, Phe or Tyr ligand) in aqueous solutions

The equilibrium constant ( K) of photochemical inversion between Δ- and Λ-[Ru( S-am)(bpy) 2] + (bpy=2, 2′- bipyridine (bpy); S-am=( S)-alaninato ( S-Ala), ( S)-phenylglycinato ( S-Phg), ( S)-leucinato ( S-Leu), ( S)-phenylalaninato ( S-Phe) or ( S)-tyrosinato ( S-Tyr) ligand) was obtained in H 2O, D 2O, CH 3OH and CH 3CNH 2O (1:1 in molar ratio) solutions at temperatures of 0 to 100 °C, and Δ H° and Δ S° were estimated. The hydrophilic solvation favored the Δ isomer in water, appearing on the enthalpy difference, and the hydrophobic solvation preferred the Λ isomer, controlling the entropy difference. These opposite effects dominated the stability of the two isomers of the complex containing the S-Leu, S-Phe or S-Tyr ligand in water. The results suggested the importance of intramolecular hydrophobic bonding. The photochemical inversion hardly occurred in pure acetonitrile.

Molecular-dynamics simulations of β- d-ribose and β- d-deoxyribose solutions

Molecular-dynamics calculations on aqueous solutions of the furanose forms of β- d-ribose and β- d-deoxyribose were carried out. Many dihedral transitions about CO bonds as well as a few changes in the ring puckering were observed. Radial and orientational distribution functions are in agreement with accepted ideas about hydrophilic and hydrophobic solvation. In comparison with water, the hydroxyl groups are better hydrogen-bond donors but worse acceptors, and the ring oxygen atom accepts even less hydrogen bonds. The diffusion constants of solute and solvent molecules are discussed. A fairly persistent local water structure about the solute molecules was observed.