This study explores the thermodynamic and vibrational properties of water in the three-dimensional environment of solvated ions and small molecules using molecular simulations. The spectrum of intermolecular vibrations in liquid solvents provides detailed information on the shape of the local potential energy surface, which in turn determines local thermodynamic properties such as the entropy. Here, we extract this information using a spatially resolved extension of the two-phase thermodynamics method to estimate hydration water entropies based on the local vibrational density of states (3D-2PT). Combined with an analysis of solute–water and water–water interaction energies, this allows us to resolve local contributions to the solvation enthalpy, entropy, and free energy. We use this approach to study effects of ions on their surrounding water hydrogen bond network, its spectrum of intermolecular vibrations, and resulting thermodynamic properties. In the three-dimensional environment of polar and nonpolar functional groups of molecular solutes, we identify distinct hydration water species and classify them by their characteristic vibrational density of states and molecular entropies. In each case, we are able to assign variations in local hydration water entropies to specific changes in the spectrum of intermolecular vibrations. This provides an important link for the thermodynamic interpretation of vibrational spectra that are accessible to far-infrared absorption and Raman spectroscopy experiments. Our analysis provides unique microscopic details regarding the hydration of hydrophobic and hydrophilic functional groups, which enable us to identify interactions and molecular degrees of freedom that determine relevant contributions to the solvation entropy and consequently the free energy.

With computational efficacy in mind, a one-center model for linear molecules is heuristically sketched. When parametrized for CO(2), all parameters save for two are supplied from literature quantum chemistry calculation or, in one case, heuristic argument. Using the remaining two adjustable parameters, the mean unsigned relative errors (predicted/observed) over the temperature range 220-290 K are 4.7% for the energy of vaporization, 0.6% for the liquid, and 8.0% for the vapor coexistence densities, respectively. The critical temperature is estimated at T(c) = 308 K, the critical density at ρ(c) = 0.460 g/cm(3), and the critical pressure at p(c) = 8.26 ± 0.11 MPa. This order of accuracy is comparable to that of many all-atom potential descriptions of CO(2) but is obtained at roughly nine times the speed. When supplied with the experimental bond length, somewhat worse agreement with experiment is exhibited for the neutron-weighted atomic pair distribution function of the liquid. This disparity is tentatively attributed to an overestimated electrostatic quadrupole-quadrupole interaction relative to the other forces present.

A number of simple pair interaction potentials of the carbon dioxide molecule are investigated and found to underestimate the magnitude of the second virial coefficient in the temperature interval 220-448 K by up to 20%. Also the third virial coefficient is underestimated by these models. A rigid, polarizable, three-site interaction potential reproduces the experimental second and third virial coefficients to within a few percent. It is based on the modified Buckingham exp-6 potential, an anisotropic Axilrod-Teller correction, and Gaussian charge densities on the atomic sites with an inducible dipole at the center of mass. The electric quadrupole moment, polarizability, and bond distances are set to equal experiment. Density of the fluid at 200 and 800 bars pressure is reproduced to within some percent of observation over the temperature range 250-310 K. The dimer structure is in passable agreement with electronically resolved quantum-mechanical calculations in the literature, as are those of the monohydrated monomer and dimer complexes using the Gaussian charge polarizable model water potential. Qualitative agreement with experiment is also obtained, when quantum corrections are included, for the relative stability of the trimer conformations, which is not the case for the pair potentials.

In view of the extreme importance of reliable computational prediction of aqueous drug solubility, we have established a Monte Carlo simulation procedure which appears, in principle, to yield reliable solubilities even for complex drug molecules. A theory based on judicious application of linear response and mean field approximations has been found to reproduce the computationally demanding free energy determinations by simulation while at the same time offering mechanistic insight. The focus here is on the suitability of the model of both drug and solvent, i.e., the force fields. The optimized potentials for liquid simulations all atom (OPLS-AA) force field, either intact or combined with partial charges determined either by semiempirical AM1/CM1A calculations or taken from the condensed-phase optimized molecular potentials for atomistic simulation studies (COMPASS) force field has been used. The results illustrate the crucial role of the force field in determining drug solubilities. The errors in interaction energies obtained by the simple force fields tested here are still found to be too large for our purpose but if a component of this error is systematic and readily removed by empirical adjustment the results are significantly improved. In fact, consistent use of the OPLS-AA Lennard-Jones force field parameters with partial charges from the COMPASS force field will in this way produce good predictions of amorphous drug solubility within 1 day on a standard desktop PC. This is shown here by the results of extensive new simulations for a total of 47 drug molecules which were also improved by increasing the water box in the hydration simulations from 500 to 2000 water molecules.

Based on the dressed-ion theory and a simple physical argument regarding the conductivity of the solution, we derive a relation between the ionic strength and dielectric constant of an electrolyte solution. At its simplest, this model gives the dielectric constant at low ionic strength I as ε(I) = ε(0)(1 + αI), where α (the excess polarization) is directly related to the dressed-ion charge. One contribution to the origin of the dielectric decrement is thus seen to stem from the electrostatic screening of the ions in solution, with no solvent contributions necessary.