Cavity Formation In Water Research Articles

Evaluation of the 1-octanol/water partition coefficient of quinolones and quinolones compounds via free energy estimated in quantum chemical calculations

A rapid screening assay for the measurement of octanol-water partition coefficients (logP) of pharmaceuticals such as quinolines, quinolones and fluoroquinolones compounds were developed by using quantum chemical calculations. In this paper, we report the logP of the pharmaceutical derivatives compounds that determined by the calculation of the difference in the solvation free energies in water-octanol using the thermodynamic integration method. The logP values calculated in this method are closer to the experimental values compared to other ab initio methods. Solvation free energy in water and octanol, free energy of cavity formation in water and Henry’s constants, and some other parameters are determined at the density functional theory (DFT) and Hartree-Fock (HF) level with 6-31++G** basis set. Moreover, surface area, mass, refractivity, volume, polarizability have been calculated for some of the compounds with the same levels.

Experimental investigation on dynamic failure of water-filled vessel subjected to projectile impact

In this investigation, a series of experiments are performed to study the deformation and failure of fluid-filled vessel subjected to high speed impact loading. The water-filled vessel with aluminum alloy target panels were impacted by the projectiles at the initial velocities of 100–300 m/s. Three different kinds of projectiles were considered to investigate the influence of nose shape of projectile on the failure modes of the water-filled tank. The high-speed photography was used to record the process of the projectile moving and the formation of cavity in water. The strain histories of target panels were measured by using the strain gauges. The results indicate that the hydrodynamic ram effect in the water-filled tank increased the damage of the target panels. The deformation of panels increased with the projectile nose coefficient (caliber-radius-head, CRH) increasing. The deformation and failure of the rear panel were more serious than those of the front panel. Additionally, the typical failure modes of the panels could be subdivided into three modes. The relationship between the kinetic energy and CRH value of the projectiles and the deformation of the panels was established.

Excess Volumes from the Pressure Derivative of the Excess Chemical Potential: Testing Simple Models for Cavity Formation in Water.

Excess volumes and excess compressibilities for hard spheres in water were computed by pressure derivatives of the excess chemical potential, which is equivalent to the work of cavity formation. This is relevant to the application of continuum solvation methods at various pressures. The excess chemical potential was modeled within phenomenological expressions for curved surfaces plus a pressure–volume term, for which two approaches were adopted, differing for the radius of the spherical volume. This implies a different dependence on pressure of parameters. In all cases, in the surface term, for the pressure derivative of parameters of the curvature function, use was made of the previously proposed expressions for the first two moments obtained from the density and radial distribution of oxygens in liquid water. Only for the parameter which has the dimension of surface tension (γ̃) was explicit dependence on pressure considered and results are affected by the specific polynomial used. In agreement with what inferred from simulation results obtained for cavities in TIP4P water, negative and positive adsorptions at the contact radius were extrapolated for a very large cavity at 1 and 8000 atm, respectively. The expressions here employed for the excess chemical potential predict the zero value of asymptotic adsorption to be at a pressure between 500 and 800 atm, which can be compared to results from the revised scaled particle theory. In the same range, for a nanometer-sized cavity, a change of behavior occurs regarding the ratio between the excess Helmholtz free energy and the product between pressure and excess volume.

The formation of a cavity in water: Changes of water distribution and prediction of the excess chemical potential of a hard-sphere solute under increasing pressure

This work deals with the formation of a spherical cavity in water along the isotherm at 298K. A striking effect of increasing pressure was found on the radial distribution functions obtained by Monte Carlo simulations, with significantly different behaviors observed when increasing the cavity radius at 8000atm and 1atm. At a fixed cavity radius, a pressure increase up to 10,000atm leads to increased hydration structure. At a constant high pressure, structure is maintained even increasing the cavity radius, while it is lost at atmospheric pressure. Particular focus is on the value at contact, G(r), the central quantity in Scaled Particle Theory that is related to the derivative with respect to the radius of the work required to form the cavity. Within the limit of very small radii, exact conditions were applied to these two quantities. This allowed us to readily determine, at any pressure along the isotherm, the parameters of a simple model used to compute the excess chemical potential associated with the hydration of a hard sphere. This was made possible thanks to heuristic models used to describe how the number density of water changes along the isotherm and how the second moment of water distribution depends on the first moment. Use was also made of additional information on a cavity of molecular size. Apart from the dependence on pressure of hydrophobic solvation, this work also concerns calculation of the so-called cavitation contribution to the free energy of solvation when this is computed within implicit solvent models.

Evaluation of the 1-octanol/water partition coefficient of nucleoside analogs via free energy estimated in quantum chemical calculations

The partition coefficients (logP) of nucleoside analogs determined by the difference in the free energies of hydration and solvation in water-saturated octanol using the thermodynamic integration method are reported. The logP values calculated in this approach are closer to the experimental values compared to other ab initio methods. Solvation free energy in water and octanol, free energy of cavity formation in water and Henry’s constants, and some other parameters are estimated at the density functional theory (DFT) and Hartree-Fock level with 6–31G*, 6–31G, and 6–31+G basis sets. Surface area, mass, refractivity, volume, polarizability, and dipole moment are calculated for some drugs with HF and DFT methods. The results show that log P decreases with the decrease in polarizability and the increase in dipole moment.

Prediction of SAMPL-1 Hydration Free Energies Using a Continuum Electrostatics-Dispersion Model

The SAMPL-1 hydration free energy blind prediction challenge data set includes 63 compounds that are more chemically diverse, polyfunctional, drug-like, and with examples of transfer free energies and molecular weights larger than ever before seen in previously tabulated data sets of neutral compounds. For the prospective SAMPL-1 study, we employed a continuum model including a boundary element solution of the Poisson equation to describe electrostatic solvation, a molecular surface area-based cost of cavity formation in water, and a continuum Lennard-Jones potential to account for dispersion-repulsion solute-solvent effects. For the latter contribution, continuum van der Waals atom-type coefficients were calibrated and validated on previously available hydration data sets. In the prospective study, this continuum hydration model yielded SAMPL-1 predictions highly correlated with experimental data, albeit with a slope of slightly above 0.5, suggesting a valid model but with a systematic error. Analysis of the major outliers, all overestimating the experimental hydration data, highlights a common structural theme as a possible cause of the prediction errors: densely polar and hydrogen-bond-capable structures, featuring primarily substituted (sulfon)amide groups, often in conjugated systems. By examining analog pairs within the SAMPL-1 data set, it was also noted that certain solvation trends are captured neither by chemical sense nor by our hydration model, which seem too additive. A retrospective analysis of model transferability between hydration data sets as a function of its parameters and complexity indicates that the electrostatic component of the model is fairly transferrable across data sets, but the nonelectrostatic terms are less so. For the chemical space covered in SAMPL-1, absolute prediction errors indicate that the simpler transferrable electrostatics-only model outperforms the more complex model including cavity and continuum dispersion terms. Possible directions to further improve this continuum hydration model are proposed.

Enthalpy−Entropy and Cavity Decomposition of Alkane Hydration Free Energies: Numerical Results and Implications for Theories of Hydrophobic Solvation

This study reports the first complete description of the solution thermodynamics of a series of linear, branched, and cyclic alkanes in water by computer simulations, including the enthalpy and entropy changes in addition to the solvation free energies. We have also obtained a complete thermodynamic description of the solvation of the associated alkane cavities. Our results lead to the following key observations: (i) The theoretical prediction that hydration entropy and solvent reorganization are weakly coupled to solute−solvent dispersion interactions is confirmed by computer simulations. (ii) The weak correlation between solute−solvent dispersion interaction energies with solute surface area explains the large relative solubilities of cyclic alkanes and the large difference between the free energy/surface area relations observed for gas to water transfer processes compared to processes involving conformational rearrangements. (iii) The work of cavity formation in water is determined in about equal meas...

Thermodynamics of cavity formation in water and n-hexane using the Widom particle insertion method

The Widom particle insertion (WPI) method is used to compute the free energy, enthalpy, and entropy associated with the creation of empty cavities of different sizes in water and n-hexane. These thermodynamic parameters are computed from the likelihood of encountering such cavities in thermally equilibrated configurations from 4 ns (1 ns=10−9 s) molecular dynamics trajectories of the neat liquids. The obtained free energy values are in excellent agreement with those computed previously, using the same or other methods. We find that the entropy term is large and unfavorable in both liquids, but more so in water than in hexane. The change in internal energy is, on the other hand, virtually zero in hexane and slightly favorable in water. Comparison with scaled particle theory (SPT) predictions shows good agreement for the free energy values for small cavities, but the theory systematically underestimates these values for large cavities. In contrast, the free energy components obtained by the two methods show several significant differences. With WPI, the entropy of cavity formation is unfavorable in both liquids for all cavity sizes. SPT yields an unfavorable entropy only for water. In hexane, however, the predicted entropy is negative for small cavities, but changes sign for cavity radii >1.1 Å. In addition, SPT yields an unfavorable enthalpy of cavity formation in water, whereas with WPI this term is small but favorable. Taking n-hexane as a model for organic solvents, our calculations thus suggest that the process of cavity formation is similar in water and these solvents, a conclusion which seems to make good physical sense. SPT reaches an opposite conclusion, which seems harder to rationalize, and probably arises from the highly simplified solvent model used by this theory.

Roles of Hydrogen Bonding and the Hard Core of Water on Hydrophobic Hydration

The roles of hydrogen bonding and the hard core of water on hydrophobic hydration are clarified using Monte Carlo simulation and the test particle method to compare the cavity formation in water with that in a Lennard-Jones (LJ) fluid with the same molecular size and density. Similarities and differences in the cavity formation in the two fluids are examined in terms of the free energy, the energy change, and the change in the coordination number upon cavity formation. The free energy of cavity formation at a given density and the decrease in the coordination number around cavities in water are similar to those in the LJ fluid. These similarities are due to geometrical restriction of the hard core of molecules. The effect of the hydrogen bonding of water can be seen in the coordination-number dependence of the average energy of one molecule, regardless of whether water is in bulk or in the hydration shell. The temperature dependence of the correlation between the coordination number and energy can explain...

Free energy of cavity formation in solvent: Computational, methodological, and physical aspects

With molecular dynamics simulation techniques, the free energy of cavity formation in water is investigated and determined at 300 K and 1 atm. Different methods are compared: Widom particle insertion, thermodynamic integration, and perturbation. It is shown that the most efficient way to get accurate results is to apply Widom particle insertion for cavities up to a thermal radius of 0.25 nm followed by a thermodynamic integration with sampling at fixed thermal radii. In order to converge the result to 2.5% at one thermal radius a simulation period in the order of 100 ps is needed. The convergence behavior for thermal radii slightly above the van der Waals radius of a water molecule (0.31 nm) is poor and thus indicates instabilities in the water shell surrounding the cavity and that the free energy is a nonsmoothly increasing function of the thermal radius.

Role of hydrogen bonds in hydrophobicity: the free energy of cavity formation in water models with and without the hydrogen bonds

The free energies of cavity formation in water with and without hydrogen bonding potential were computed from the results of a set of Monte Carlo simulation calculations on pure liquid TIP4P water model and on the same model but with the electrostatic charges turned off (Lennard-Jones liquid). The free energies of cavity formation in the Lennard-Jones liquids are higher than or approximately equal to those in TIP4P water, depending, respectively, on whether the Lennard-Jones size parameter σ is set equal to 3.15A˚, which is the value of σ for TIP4P water, or to 2.8A˚, which is the commonly assumed value for the oxygen—oxygen distance between two hydrogen-bonded water molecules. This result indicates that changes in the hydrogen-bonded structure of water and/or in the orientational degree of freedom of water are not essential features in the production of the large free energy change upon cavity formation.

Estimation of the maximum change in stability of globular proteins upon mutation of a hydrophobic residue to another of smaller size

Although the hydrophobic effect is generally considered to be one of the most important forces in stabilizing the folded structure of a globular protein molecule, there is a lack of consensus on the precise magnitude of this effect. The magnitude of the hydrophobic effect is most directly measured by observing the change in stability of a protein molecule when an internal hydrophobic residue is mutated to another of smaller size. Results of such measurements have, however, been confusing because they vary greatly and are generally considerably larger than expected from the transfer free energies of corresponding small molecules. In this article, a thermodynamic argument is presented to show (1) that the variation is mainly due to that in the flexibility of the protein molecule at the site of mutation, (2) that the maximum destabilization occurs when the protein at the site of mutation is rigid, in which case the value of the destabilization is approximately given by the work of cavity formation in water, and (3) that the transfer free energy approximately gives the minimum of the range of variations. The best numerical agreements between the small molecule and the protein systems are obtained when the data from the small molecule system are expressed as the molarity-based standard free energies without other corrections.

System Relaxation and Thermodynamic Integration

The thermodynamic integration (TI) method for calculating free energy differences has three inherent problems: statistics, numerical integration, and relaxation. In this paper the latter is analyzed for the nonequilibrium TI method introduced by Postma which combines molecular dynamics simulation and TI in a very effective way. A nontrivial extrapolation technique is presented to remove the relaxation error and to calculate the underlying relaxation time. It is shown that the optimal choice of grid points, derived in a previous paper, for minimizing statistical errors not only removes integration errors, but also minimizes relaxation errors. The methods are applied in a calculation of the free energy of cavity formation in water.

Surface tension measurements show that chaotropic salting-in denaturants are not just water-structure breakers.

Since the salting-in agents guanidinium chloride, urea, and lithium perchlorate increase the surface tension of water, the salting-in phenomenon does not reflect easier cavity formation in water. Therefore, these salting-in agents must be directly contributing to the solvation of a solute such as benzene in water, probably by a direct solvation interaction. The increased surface-tension effects do not overbalance these solvation effects since they are smaller than the large surface-tension increases with lithium chloride, a typical salting-out agent. The salting-in agent tetra-n-butylammonium chloride differs in that it lowers the surface tension of water. Thus, it probably contributes both to easier cavity formation and to direct solvation of the substrate. The previous findings that most salting-in agents switch to become salting-out agents in other polar solvents such as ethylene glycol and formamide but that tetra-n-butylammonium chloride does not switch in these solvents can be understood in terms of relative polarities.

Thermodynamics of cavity formation in water. A molecular dynamics study

Thermodynamic quantities related to the solvation of hydrophobic solutes in water can be approximated by the application of scaled-particle theory. The crucial quantity is the Gibbs free energy of cavity formation. A series of six molecular-dynamics simulations of water including repulsive cavities of various sizes has been carried out. Using perturbation statistical mechanics, the free energy has been derived as a function of cavity radius up to 0.32 nm (0.32 nm approach of water oxygens to the cavity centre). The free energy agrees well with predictions from scaled-particle theory and the experimental surface tension is predicted to within 5%. The radial distribution of water molecules with respect to the cavity has been determined for five cavity sizes; for one size (radius of approach of water oxygens of 0.3 nm) the orientational distribution and the residence-time distribution in the hydration shells has been determined.

On Cavity Formation in Water

Phenomena involving the tensile strength of water have been studied by a kinetic method—high speed motion photography of the rapid movement of a blunt glass rod (5 mm diameter) in a narrow (16 mm inside diameter) glass tube of water. Special precautions have been taken to remove all hydrophobic patches and small gas masses (gas nuclei) but to retain the dissolved gas (air at one atmosphere) in the water. If the rod surface contained gas nuclei, or was hydrophobic and free of gas nuclei, cavitation occurred at the rear end when the velocity was less than 3 meters/sec., but if completely hydrophilic and free of gas nuclei, the velocity could be 37 meters/sec. or 83 miles/hour without cavitation. Addition of a detergent (diactyl sodium succinate) to the water did not prevent cavitation at a low velocity with the hydrophobic rod free of gas nuclei. Movement of a rod in pure corn syrup (viscosity 20.1 poises), free of gas nuclei, left a large cylindrical cavity that collapsed in a matter of hundredths of a second. It is not possible to calculate the tensions developed in these experiments, but it is pointed out that the velocities attained without cavitation are far higher than previously observed for movement of bodies in an aqueous medium, a result believed to be owing to the absence of all gas phases and hydrophobic surfaces.