On the heat-capacity change of pairwise hydrophobic interactions

Computer simulations [S. Shimizu and H. S. Chan, J. Am. Chem. Soc. 123, 2083 (2001); D. Paschek, J. Chem. Phys. 120, 10605 (2004)] have demonstrated that the heat-capacity change associated with the interaction of two nonpolar spherical particles, at room temperature, shows a complex behavior with a significant maximum at the distance corresponding to the desolvation barrier configuration and a small minimum at the distance corresponding to the contact configuration. Taking advantage of the detailed analysis performed by Paschek, the two-state model of Muller is applied to estimate the energetic strength and the intactness of the H bonds in the hydration shell of a xenon atom and in the concave part of the joint Xe-Xe hydration shell. In both hydration shell regions the H bonds are energetically stronger but more broken than those in bulk water. In addition, those in the concave part of the joint Xe-Xe hydration shell are, in absolute, stronger and more broken. These thermodynamic features coupled to simple geometric arguments allow the calculation of heat-capacity values that are in agreement with those provided by computer simulations for the pairwise Xe-Xe interaction.     

Potential of mean force of hydrophobic association: dependence on solute size

The potentials of mean force (PMFs) were determined for systems involving formation of nonpolar dimers composed of methane, ethane, propane, isobutane, and neopentane, respectively, in water, using the TIP3P water model, and in vacuo. A series of umbrella-sampling molecular dynamics simulations with the AMBER force field was carried out for each pair in either water or in vacuo. The PMFs were calculated by using the weighted histogram analysis method (WHAM). The shape of the PMFs for dimers of all five nonpolar molecules is characteristic of hydrophobic interactions with contact and solvent-separated minima and desolvation maxima. The positions of all these minima and maxima change with the size of the nonpolar molecule, that is, for larger molecules they shift toward larger distances. The PMF of the neopentane dimer is similar to those of other small nonpolar molecules studied in this work, and hence the neopentane dimer is too small to be treated as a nanoscale hydrophobic object. The solvent contribution to the PMF was also computed by subtracting the PMF determined in vacuo from the PMF in explicit solvent. The molecular surface area model correctly describes the solvent contribution to the PMF together with the changes of the height and positions of the desolvation barrier for all dimers investigated. The water molecules in the first solvation sphere of the dimer are more ordered compared to bulk water, with their dipole moments pointing away from the surface of the dimer. The average number of hydrogen bonds per water molecule in this first hydration shell is smaller compared to that in bulk water, which can be explained by coordination of water molecules to the hydrocarbon surface. In the second hydration shell, the average number of hydrogen bonds is greater compared to bulk water, which can be explained by increased ordering of water from the first hydration shell; the net effect is more efficient hydrogen bonding between the water molecules in the first and second hydration shells.     

High-density hydration layer of lysozymes: molecular dynamics decomposition of solution scattering data

A characterization of the physical properties of protein hydration water is critical for understanding protein structure and function. Recent small-angle X-ray and neutron scattering data indicate that the density of water on the surface of lysozyme is significantly higher than in bulk water. Here, we provide an interpretation of the scattering results using a molecular dynamics simulation, which allows us to make quantitative predictions about density variations in the first hydration shell. The perturbation relative to bulk water involves statistically significant changes in the average water structure in the first hydration layer. The water density in the first hydration shell is increased by 5% with respect to the bulk. In regions of higher water density, the water dipoles align more parallel to each other and the number of hydrogen bonds per water molecule is higher. Increased water density is found for water molecules interacting with hydrogen and carbon atoms in the backbone or with nonpolar or negatively charged side-chain groups.     

Towards an understanding of the molecular basis of hydrophobicity

Summary The modern view is stressed that the structuring of water around nonpolar solutes, a process called hydrophobic hydration, actually favors the solubility of nonpolar solutes in water, its associated positive free energy of transfer arising from the enthalpic input required to create a cavity in water to accommodate the solute. The results of a series of molecular dynamics simulations of methane in SPC/E water at different temperatures are reported. These results show the existence of a larger fraction of broken hydrogen bonds in the hydration-shell water of the nonpolar solutes with respect to the bulk water, the difference increasing with a rise in temperature. This supports Muller's modified hydration-shell hydrogen-bond model predictions, where hydration-shell water molecules have lower free energies of hydrogen-bond breaking than those in the bulk.This paper is based on a presentation given at the 14th Molecular Graphics and Modelling Society Conference, held in Cairns, Australia, August 27 September 1, 1995.     

Solvent-exposed backbone loosens the hydration shell of soluble folded proteins

The hydration shell of a soluble folded protein is not uniform: its tightness, marked by the mobility of interfacial water, is site dependent and modulates the propensity for protein associations. We found that the most pronounced interfacial dehydration propensity for representative folds is promoted by solvent-exposed intramolecular hydrogen bonds that are incompletely shielded from water attack. These bonds are poorly wrapped by surrounding nonpolar groups from the side chains and their dehydration is energetically favored.     

The effect of aqueous solutions of trimethylamine-N-oxide on pressure induced modifications of hydrophobic interactions

To understand the mechanism of protein protection by the osmolyte trimethylamine-N-oxide (TMAO) at high pressure, using molecular dynamics (MD) simulations, solvation of hydrophobic group is probed in aqueous solutions of TMAO over a wide range of pressures relevant to protein denaturation. The hydrophobic solute considered in this study is neopentane which is a considerably large molecule. The concentrations of TMAO range from 0 to 4 M and for each TMAO concentration, simulations are performed at five different pressures ranging from 1 atm to 8000 atm. Potentials of mean force are calculated and the relative stability of solvent-separated state over the associated state of hydrophobic solute are estimated. Results suggest that high pressure reduces association of hydrophobic solutes. From computations of site-site radial distribution function followed by analysis of coordination number, it is found that water molecules are tightly packed around the nonpolar particle at high pressure and the hydration number increases with increasing pressure. On the other hand, neopentane interacts preferentially with TMAO over water and although hydration of neopentane reduces in presence of this osmolyte, TMAO does not show any tendency to prevent the pressure-induced dispersion of neopentane moieties. It is also observed that TMAO molecules prefer a side-on orientation near the neopentane surface, allowing its oxygen atom to form favorable hydrogen bonds with water while maintaining some hydrophobic contacts with neopentane. Analysis of hydrogen-bond properties and solvation characteristics of TMAO reveals that TMAO can form hydrogen bonds with water and it reduces the identical nearest neighbor water molecules caused by high hydrostatic pressures. Moreover, TMAO enhances life-time of water-water hydrogen bonds and makes these hydrogen bonds more attractive. Implication of these results for counteracting effect of TMAO against protein denaturation at high pressures are discussed.     

How ions affect the structure of water

We model ion solvation in water. We use the MB model of water, a simple two-dimensional statistical mechanical model in which waters are represented as Lennard-Jones disks having Gaussian hydrogen-bonding arms. We introduce a charge dipole into MB waters. We perform (NPT) Monte Carlo simulations to explore how water molecules are organized around ions and around nonpolar solutes in salt solutions. The model gives good qualitative agreement with experiments, including Jones-Dole viscosity B coefficients, Samoilov and Hirata ion hydration activation energies, ion solvation thermodynamics, and Setschenow coefficients for Hofmeister series ions, which describe the salt concentration dependence of the solubilities of hydrophobic solutes. The two main ideas captured here are (1) that charge densities govern the interactions of ions with water, and (2) that a balance of forces determines water structure: electrostatics (water's dipole interacting with ions) and hydrogen bonding (water interacting with neighboring waters). Small ions (kosmotropes) have high charge densities so they cause strong electrostatic ordering of nearby waters, breaking hydrogen bonds. In contrast, large ions (chaotropes) have low charge densities, and surrounding water molecules are largely hydrogen bonded.     

Local heterogeneous dynamics of water around lysozyme: a computer simulation study

Water present near the surface of a protein exhibits dynamic properties different from that of water in the pure bulk state. In this work, we have carried out atomistic molecular dynamics simulation of an aqueous solution of hen egg-white lysozyme. Attempts have been made to explore the correlation between the local heterogeneous mobility of water around the protein segments and the rigidity of the hydration layers with the microscopic dynamics of hydrogen bonds formed by water molecules with the protein residues. The kinetics of breaking and reformation of hydrogen bonds involving the surface water molecules have been calculated. It is found that the reformations of broken hydrogen bonds are more frequent for the hydration layers of those segments of the protein that are more rigid. The calculation of the low-frequency vibrational modes of hydration layer water molecules reveals that the protein influences the transverse and longitudinal degrees of freedom of water around it in a differential manner. These findings can be verified by appropriate experimental studies.     

Microwave dielectric permittivity and relaxation of aqueous potassium trimethylacetate solutions

The MW dielectric properties of aqueous potassium trimethylacetate (pivalate) solutions have been measured at six frequencies (10–25 GHz) at 288, 298, and 308 K. The static dielectric constants and dielectric relaxation times and activation parameters have been calculated. Trimethylacetate ion leads to the decrease in the mobility of water molecules and strengthening of their hydrogen bonds. These changes of water are similar to those in solutions of other carboxylates with a large number of nonpolar groups. The hydrophobic hydration of the trimethylacetate ion is maximal in this series.     

Low-frequency vibrational spectrum of water in the hydration layer of a protein: a molecular dynamics simulation study

An atomistic molecular dynamics simulation has been carried out to understand the low-frequency intermolecular vibrational spectrum of water present in the hydration layer of the protein villin headpiece subdomain or HP-36. An attempt is made to explore how the heterogeneous rigidity of the hydration layers of different segments (three alpha helices) of the protein, strength of the protein-water hydrogen bonds, and their differential relaxation behavior influence the distribution of the intermolecular vibrational density of states of water in the hydration layers. The calculations revealed that compared to bulk water these bands are nonuniformly blue-shifted for water near the helices, the extent of shifts being more pronounced for water molecules hydrogen bonded to the protein residues. It is further noticed that the larger blue shift observed for the water molecules hydrogen bonded to helix 2 residues correlates excellently with the slowest structural relaxation of these hydrogen bonds. These results can be verified by suitable experimental measurements.     

The hydration of glucose: the local configurations in sugar-water hydrogen bonds

The hydration of a simple sugar is an essential model for understanding interactions between hydrophilic groups and interfacial water molecules. Here I perform first-principles molecular dynamics simulations on a glucose-water system and investigate how individual hydroxyl groups are locally hydrated. I demonstrate that the hydroxyl groups are less hydrated and more incompatible with a locally tetrahedral network of hydrogen bonds than previously thought. The results suggest that the hydroxyl groups form roughly two hydrogen bonds. Further, I find that the local hydration of the hydroxyl groups is sensitively affected by seemingly small variations in the local electronic structure and bond polarity of the groups. My findings offer insight into an atomic-level understanding of sugar-water interactions.     

The SGB/NP hydration free energy model based on the surface generalized born solvent reaction field and novel nonpolar hydration free energy estimators

The development and parameterization of a solvent potential of mean force designed to reproduce the hydration thermodynamics of small molecules and macromolecules aimed toward applications in conformation prediction and ligand binding free energy prediction is presented. The model, named SGB/NP, is based on a parameterization of the Surface Generalized Born continuum dielectric electrostatic model using explicit solvent free energy perturbation calculations and a newly developed nonpolar hydration free energy estimator motivated by the results of explicit solvent simulations of the thermodynamics of hydration of hydrocarbons. The nonpolar model contains, in addition to the more commonly used solvent accessible surface area term, a component corresponding to the attractive solute-solvent interactions. This term is found to be important to improve the accuracy of the model, particularly for cyclic and hydrogen bonding compounds. The model is parameterized against the experimental hydration free energies of a set of small organic molecules. The model reproduces the experimental hydration free energies of small organic molecules with an accuracy comparable or superior to similar models employing more computationally demanding estimators and/or a more extensive set of parameters.     

Hydrophobic hydration in an orientational lattice model

To shed light on the microscopic mechanism of hydrophobic hydration, we study a simplified lattice model for water solutions in which the orientational nature of hydrogen bonding as well as the degeneracy related to proton distribution are taken into account. Miscibility properties of the model are looked at for both polar (hydrogen bonding) and nonpolar (non-hydrogen bonding) solutes. A quasichemical solution for the pure system is reviewed and extended to include the different kinds of solute. A Monte Carlo study of our model yields a novel feature for the local structure of the hydration layer: energy correlation relaxation times for solvation water are larger than the corresponding relaxation times for bulk water. This result suggests the presence of ordering of water particles in the first hydration shell. A nonassociating model solvent, represented by a lattice gas, presents opposite behavior, indicating that this effect is a result of the directionality of the interaction. In presence of polar solutes, we find an ordered mixed pseudophase at low temperatures, indicating the possibility of closed loops of immiscibility.     

Secondary structure sensitivity of hydrogen bond lifetime dynamics in the protein hydration layer

The heterogeneous nature of a protein surface plays an essential role in its biological activity and molecular recognition, and this role is mediated at least partly through the surrounding water molecules. We have performed atomistic molecular dynamics simulations of an aqueous solution of HP-36 to investigate the correlation between the dynamics of the hydration layer water molecules and the lifetimes of protein-water hydrogen bonds. The nonexponential hydrogen bond lifetime correlation functions have been analyzed by using the formalism of Luzar and Chandler, which allowed identification of the quasi-bound states in the surface and quantification of the dynamic equilibrium between quasi-bound and free water molecules in terms of time-dependent rate of interconversion. It is noticed that, irrespective of the structural heterogeneity of different segments of the protein, namely the three alpha-helices, the positively charged amino acid residues form longer-lived hydrogen bonds with water. The overall relaxation behavior of protein-water hydrogen bonds is found to differ significantly among the three helices of the protein. Study of water number density fluctuation reveals that the hydration layer of helix-3 is much less rigid, which can be correlated with faster structural relaxation of the hydrogen bonds between its residues and water. This also agrees excellently with faster translational and rotational motions of water near helix-3, and hence the lower rigidity of its hydration layer. The lower rigidity of the helix-3 hydration layer also correlates well with the biological activity of the protein, as several of the active-site residues of HP-36 are located in helix-3.     

Hydration-induced changes of structure and vibrational frequencies of methylphosphocholine studied as a model of biomembrane lipids

The chemical characteristics of the polar parts of phospholipids as the main components of biological membranes were investigated by using infrared (IR) spectroscopy and theoretical calculations with water as a probe molecule. The logical key molecule used in this study is methylphosphocholine (MePC) as it is not only a representative model for a polar lipid headgroup but itself has biological significance. Isolated MePC forms a compact (folded) structure which is essentially stabilized by two intramolecular C-H...O type hydrogen bonds. At lower hydration, considerable wavenumber shifts were revealed by IR spectroscopy: the frequencies of the (O-P-O)- stretches were strongly redshifted, whereas methyl and methylene C-H and O-P-O stretches shifted surprisingly to blue. The origin of both red- and blueshifts was rationalized, on the basis of molecular-dynamics and quantum-chemistry calculations. In more detail, the hydration-induced blueshifts of C-H stretches could be shown to arise from several origins: disruption of the intramolecular C-H...O hydrogen bonds, formation of intermolecular C-H...O(water) H-bonds. The stepwise disruption of the intramolecular hydrogen bonds appeared to be the main feature that causes partial unfolding of the compact structure. However, the transition from a folded to extended MePC structure was completed only at high hydration. One might hypothesize that the mechanism of hydration-driven conformational changes as described here for MePC could be transferred to other zwitterions with relevant internal C-H...O hydrogen bonds.     

Water's hydrogen bonds in the hydrophobic effect: a simple model

We propose a simple analytical model to account for water's hydrogen bonds in the hydrophobic effect. It is based on computing a mean-field partition function for a water molecule in the first solvation shell around a solute molecule. The model treats the orientational restrictions from hydrogen bonding, and utilizes quantities that can be obtained from bulk water simulations. We illustrate the principles in a 2-dimensional Mercedes-Benz-like model. Our model gives good predictions for the heat capacity of hydrophobic solvation, reproduces the solvation energies and entropies at different temperatures with only one fitting parameter, and accounts for the solute size dependence of the hydrophobic effect. Our model supports the view that water's hydrogen bonding propensity determines the temperature dependence of the hydrophobic effect. It explains the puzzling experimental observation that dissolving a nonpolar solute in hot water has positive entropy.     

Water-induced folding of 1,7-diammoniumheptane

Effects of hydration on the gaseous structures of diprotonated 1,7-diaminoheptane and protonated heptylamine are investigated by infrared photodissociation (IRPD) spectroscopy and computational chemistry. IRPD spectra in the hydrogen bond stretching region (2800-3900 cm(-1)) indicate that 1,7-diammoniumheptane is linear and that hydration occurs predominantly by alternate solvation of the two protonated amine groups for clusters with up to 10 water molecules. The relative intensities of bonded versus free hydroxyl (OH) stretches are greater in the spectra of 1,7-diammoniumheptane with more than 12 water molecules attached than the corresponding reference spectra of heptylammonium. This indicates that in the larger clusters, 1,7-diammoniumheptane adopts a more folded conformation in which the two protonated amine groups are solvated by a single water nanodrop. These results are supported by molecular dynamics simulations which show more hydrogen bonds in representative folded structures of hydrated 1,7-diammoniumheptane versus those with linear structures. These results indicate that the increase in Coulomb energy as a result of bringing the two positive charges closer together in the folded structures is compensated for by the additional hydrogen bonds that are possible when a single nanodrop solvates both protonated amine groups.     

Hydrogen bond lifetime dynamics at the interface of a surfactant monolayer

The dynamics of water near the polar headgroups of surfactants in a monolayer adsorbed at the air/water interface is likely to play a decisive role in determining the physical behavior of such organized assemblies. We have carried out an atomistic molecular dynamics (MD) simulation of a monolayer of the anionic surfactant sodium bis(2-ethyl-1-hexyl) sulfosuccinate (aerosol-OT or AOT) adsorbed at the air/water interface. The simulation is performed at room temperature with a surface coverage of that at the critical micelle concentration (78 Angstrom(2)/molecule). Detailed analyses of the lifetime dynamics of surfactant-water (SW) and water-water (WW) hydrogen bonds at the interface have been carried out. The nonexponential hydrogen bond lifetime correlation functions have been analyzed by using the formalism of Luzar and Chandler, which allowed identification of the bound states at the interface and quantification of the dynamic equilibrium between bound and quasi-free water molecules, in terms of time-dependent relaxation rates. It is observed that the water molecules present in the first hydration layer form strong hydrogen bonds with the surfactant headgroups and hence have longer lifetimes. Importantly, it is found that the overall relaxation of the SW hydrogen bonds is faster for those water molecules which form two hydrogen bonds with the surfactant headgroups than those forming one such hydrogen bond. Equally interestingly, it is further noticed that water molecules beyond the first hydration layer form weaker hydrogen bonds than pure bulk water.     

Classical molecular-dynamics simulation of the hydroxyl radical in water

We have studied the hydration and diffusion of the hydroxyl radical OH0 in water using classical molecular dynamics. We report the atomic radial distribution functions, hydrogen-bond distributions, angular distribution functions, and lifetimes of the hydration structures. The most frequent hydration structure in the OH0 has one water molecule bound to the OH0 oxygen (57% of the time), and one water molecule bound to the OH0 hydrogen (88% of the time). In the hydrogen bonds between the OH0 and the water that surrounds it the OH0 acts mainly as proton donor. These hydrogen bonds take place in a low percentage, indicating little adaptability of the molecule to the structure of the solvent. All hydration structures of the OH0 have shorter lifetimes than those corresponding to the hydration structures of the water molecule. The value of the diffusion coefficient of the OH0 obtained from the simulation was 7.1x10(-9) m2 s(-1), which is higher than those of the water and the OH-.