Entropy Of Water Molecules Research Articles

Understanding the Hydration Thermodynamics of Cationic Quaternary Ammonium and Charge-Neutral Amine Surfactants.

Aqueous solubility and interfacial adsorption of surfactants are important for numerous applications. Using molecular dynamics, we have studied the effect of the type of the polar headgroup (cationic quaternary ammonium and charge-neutral amine) and length of the alkyl tail on the hydration free energy of surfactants in infinite dilution. In addition, we have studied the effect of replacing the terminal methyl group of the alkyl tail with a more polar hydroxyl group on the hydration free energy. Quaternary ammonium surfactants have strongly favorable hydration free energies, whereas charge-neutral amine surfactants have unfavorable hydration free energies. The contribution of the quaternary ammonium group in reducing the hydration free energy is estimated to be as large as ∼63 kBT and that of the charge-neutral amine group to be 3 kBT. Both surfactants and their corresponding alkanes have minima in the free energy at the air-water interface. The quaternary ammonium group contributes to a 6 kBT decrease in the free energy of transfer from air-water interface to bulk aqueous phase (termed henceforth as interface transfer free energy). The amine group, on the other hand, has a net zero interface transfer free energy. The interface transfer free energies of surfactants are both enthalpically and entropically unfavorable. The enthalpic penalty is attributed to the loss of water-water interactions. Interestingly, surfactant molecules gain entropy upon their transfer from the air-water interface to the aqueous phase, but this increase is more than compensated by the loss in the entropy of water molecules, presumably due to the ordering of water molecules around the surfactants. Replacing the terminal methyl group of the alkyl tail with a hydroxyl group in quat surfactants reduces their hydration free energy by 10 kBT, thus making them more soluble in water. Attaching a hydroxyl group to the alkyl tail also inhibits their micelle forming tendency in the bulk aqueous phase. Overall, this work reveals how tuning the molecular characteristics of surfactants can help to achieve the desirable aqueous solubility, interfacial properties, and micellization tendency of surfactants.

Assessment of Hydration Thermodynamics at Protein Interfaces with Grid Cell Theory.

Molecular dynamics simulations have been analyzed with the Grid Cell Theory (GCT) method to spatially resolve the binding enthalpies and entropies of water molecules at the interface of 17 structurally diverse proteins. Correlations between computed energetics and structural descriptors have been sought to facilitate the development of simple models of protein hydration. Little correlation was found between GCT-computed binding enthalpies and continuum electrostatics calculations. A simple count of contacts with functional groups in charged amino acids correlates well with enhanced water stabilization, but the stability of water near hydrophobic and polar residues depends markedly on its coordination environment. The positions of X-ray-resolved water molecules correlate with computed high-density hydration sites, but many unresolved waters are significantly stabilized at the protein surfaces. A defining characteristic of ligand-binding pockets compared to nonbinding pockets was a greater solvent-accessible volume, but average water thermodynamic properties were not distinctive from other interfacial regions. Interfacial water molecules are frequently stabilized by enthalpy and destabilized entropy with respect to bulk, but counter-examples occasionally occur. Overall detailed inspection of the local coordinating environment appears necessary to gauge the thermodynamic stability of water in protein structures.

Pairwise association of neopentane as a function of hydrostatic pressure

It is shown that the contact-minimum configuration of two neopentane molecules is favoured on increasing hydrostatic pressure over the range 1–4000atm, at room temperature, in line with the methane results (Graziano, 2014). This is due to the decrease in water accessible surface area accompanying the association, that leads to a gain in configurational/translational entropy of water molecules, whose magnitude increases with hydrostatic pressure. Of course, the strengthening of pairwise hydrophobic interaction cannot shed light on the pressure-induced denaturation of globular proteins.

Hydrostatic pressure effect on hydrophobic hydration and pairwise hydrophobic interaction of methane

At room temperature, the Ben-Naim standard hydration Gibbs energy of methane is a positive quantity that increases markedly with hydrostatic pressure [M. S. Moghaddam and H. S. Chan, J. Chem. Phys. 126, 114507 (2007)]. This finding is rationalized by showing that the magnitude of the reversible work to create a suitable cavity in water increases with pressure due to both the increase in the volume packing density of water and the contribution of the pressure-volume work. According to the present approach, at room temperature, the Gibbs energy of the contact-minimum configuration of two methane molecules is a negative quantity that increases in magnitude with hydrostatic pressure. This result is not in line with the results of several computer simulation studies [T. Ghosh, A. E. Garcia, and S. Garde, J. Am. Chem. Soc. 123, 10997-11003 (2001)], and emerges because pairwise association causes a decrease in solvent-excluded volume that produces a gain of configurational/translational entropy of water molecules, whose magnitude increases with the volume packing density of the liquid phase.

Prediction of Small Molecule Hydration Thermodynamics with Grid Cell Theory

An efficient methodology has been developed to quantify water energetics by analysis of explicit solvent molecular simulations of organic and biomolecular systems. The approach, grid cell theory (GCT), relies on a discretization of the cell theory methodology on a three-dimensional grid to spatially resolve the density, enthalpy, and entropy of water molecules in the vicinity of solute(s) of interest. Entropies of hydration are found to converge more efficiently than enthalpies of hydration. GCT predictions of free energies of hydration on a data set of small molecules are strongly correlated with thermodynamic integration predictions. Agreement with the experiment is comparable for both approaches. A key advantage of GCT is its ability to provide from a single simulation insightful graphical analyses of spatially resolved components of the enthalpies and entropies of hydration.

Accurate Predictions of Nonpolar Solvation Free Energies Require Explicit Consideration of Binding-Site Hydration

Continuum solvation methods are frequently used to increase the efficiency of computational methods to estimate free energies. In this paper, we have evaluated how well such methods estimate the nonpolar solvation free-energy change when a ligand binds to a protein. Three different continuum methods at various levels of approximation were considered, viz., the polarized continuum model (PCM), a method based on cavity and dispersion terms (CD), and a method based on a linear relation to the solvent-accessible surface area (SASA). Formally rigorous double-decoupling thermodynamic integration was used as a benchmark for the continuum methods. We have studied four protein-ligand complexes with binding sites of varying solvent exposure, namely the binding of phenol to ferritin, a biotin analogue to avidin, 2-aminobenzimidazole to trypsin, and a substituted galactoside to galectin-3. For ferritin and avidin, which have relatively hidden binding sites, rather accurate nonpolar solvation free energies could be obtained with the continuum methods if the binding site is prohibited to be filled by continuum water in the unbound state, even though the simulations and experiments show that the ligand replaces several water molecules upon binding. For the more solvent exposed binding sites of trypsin and galectin-3, no accurate continuum estimates could be obtained, even if the binding site was allowed or prohibited to be filled by continuum water. This shows that continuum methods fail to give accurate free energies on a wide range of systems with varying solvent exposure because they lack a microscopic picture of binding-site hydration as well as information about the entropy of water molecules that are in the binding site before the ligand binds. Consequently, binding affinity estimates based upon continuum solvation methods will give absolute binding energies that may differ by up to 200 kJ/mol depending on the method used. Moreover, even relative energies between ligands with the same scaffold may differ by up to 75 kJ/mol. We have tried to improve the continuum solvation methods by adding information about the solvent exposure of the binding site or the hydration of the binding site, and the results are promising at least for this small set of complexes.

Cold unfolding of β‐hairpins: A molecular‐level rationalization

Isolated β-hairpins in water have a temperature dependence of their conformational stability qualitatively resembling that of globular proteins, showing both cold and hot unfolding transitions. It is shown that a molecular-level rationalization of this cold unfolding can be provided extending the approach devised for globular proteins (Graziano G. Phys Chem Chem Phys 2010; 12:14245-14252). The decrease in the solvent-excluded volume upon folding, measured by the decrease in the solvent accessible surface area, produces a gain in configurational/translational entropy of water molecules that is the main stabilizing contribution of the folded conformation. This always stabilizing Gibbs energy contribution has a parabolic-like temperature dependence in water and is exactly counterbalanced at two temperatures (i.e., the cold and hot unfolding temperatures) by the always destabilizing Gibbs energy contribution due to the loss in conformational degrees of freedom of the peptide chain.

On the pairwise hydrophobic interaction of fullerene

Makowski et al. [9] determined the potential of mean force for the association of two fullerene molecules in TIP3P water, at room temperature, and found that the water contribution contrasts pairwise hydrophobic interaction. In the present Letter this result is rationalized by showing that the decrease in water accessible surface area upon association causes both a gain in configurational/translational entropy of water molecules and a loss of a significant fraction of fullerene–water attractive energetic interactions. The latter term proves to be larger in magnitude than the former because the carbon atom density on fullerene molecular surface is markedly greater than that of normal hydrocarbons.

Free Energies and Entropies of Water Molecules at the Inhibitor−Protein Interface of DNA Gyrase

Complexes of the antibiotics novobiocin and clorobiocin with DNA gyrase are illustrative of the importance of bound water to binding thermodynamics. Mutants resistant to novobiocin as well as those with a decreased affinity for novobiocin over clorobiocin both involve a less favorable entropy of binding, which more than compensates for a more favorable enthalpy, and additional water molecules at the protein-ligand interface. Free energy, enthalpy, and entropy for these water molecules were calculated by thermodynamic integration computer simulations. The calculations show that addition of the water molecules is entropically unfavorable, with values that are comparable to the measured entropy differences. The free energies and entropies correlate with the change in the number of hydrogen bonds due to the addition of water molecules.