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The solvation free energy of polar and nonpolar molecules in water is examined using the statistical mechanical integral equation theory which was recently introduced by Beglov and Roux (J. Phys. Chem. 1997, 101, 7821). The integral equation is an extension of previous theories based on the reference interaction site model (RISM) and the hypernetted chain equation (HNC) to determine the one-dimensional site−site radial pair correlation functions. Since the integral equation provides the average density of the solvent interaction sites in three-dimensional (3d) space around a complex molecular solute of arbitrary shape, it is thereby referred to as the 3d-RISM-HNC integral equation. In the present paper, the accuracy of the 3d-RISM-HNC integral equation is examined by comparing the calculated excess solvation free energy at infinite dilution with experimental data for a set of nonpolar (n-alkanes) and polar (n-alcohols, n-carboxylic acids, and simple amides) molecules. Thermodynamic integration is used to calculate the excess solvation free energy on the basis of the average site densities obtained by the 3d-RISM-HNC equation. Two extensions were made to improve the accuracy of the integral equation. First, the susceptibility of pure liquid water (an input for calculating the excess solvation free energy of molecules in the infinite dilution limit) was obtained by combining information from a molecular dynamics simulation with the RISM-HNC integral equation. Second, empirical water hydrogen and water oxygen bridge functions were introduced and optimized for improving the accuracy of the theory. The calculated solvation free energies are in good accord with experimental data, although further work will be required for quantitatively accurate results. These preliminary results indicate that the 3d-RISM-HNC equation with well-calibrated optimized bridge functions is a promising approach for calculating the hydration free energy of complex molecules.

We developed and implemented a statistical mechanical integral equation theory to describe the hydration structure of complex molecules. The theory, which is an extension of the reference interaction site model (RISM) in three dimensions, yields the average density from the solvent interactions sites at all points r around a molecular solute of arbitrary shape. Both solute−solvent electrostatic and van der Waals interactions are fully included, and solvent packing is taken into account. The approach is illustrated by calculating the average oxygen and hydrogen density of liquid water around two molecular solutes:  water and N-methylacetamide. Molecular dynamics simulations are performed to test the results obtained from the integral equation. It is observed that important microscopic structural features of the average water density due to hydrogen bonding are reproduced by the integral equation. The integral equation has a simple formal structure and is easy to implement numerically. It offers a powerful alternative to computer simulations with explicit solvent molecules and to continuum solvent representations for incorporating solvation effects in a wide range of applications.

The electrostatic contribution to the solvation free energy of the 20 naturally occurring amino acids is examined using atomic models. The amino acids are modeled by N-acetyl-X-N‘-methylamide. Free energy perturbation techniques with explicit water molecules are used to evaluate the contribution of solute−solvent electrostatic interactions to the solvation free energies. An analysis based on the radial solvent charge distribution yields a basic rule to determine a set of atomic Born radii defining the dielectric boundary between the solute and the solvent in continuum electrostatic models. Minor adjustments are made to refine the atomic Born radii in order to reproduce quantitatively the electrostatic contribution to the solvation free energy calculated by free energy perturbation techniques. The good agreement of continuum electrostatic and molecular dynamics free energy perturbations suggests that the new set of atomic Born radii may be used as a computationally inexpensive alternative to the microscopic treatment of solvent with explicit water molecules.

Formaldehyde has long been recognized as a hazardous environmental agent highly reactive with DNA. Recently, it has been realized that due to the activity of histone demethylation enzymes within the cell nucleus, formaldehyde is produced endogenously in direct vicinity of genomic DNA. Should it lead to extensive DNA damage? We address this question with the aid of a computational mapping method, analogous to X-ray and nuclear magnetic resonance techniques for observing weakly specific interactions of small organic compounds with a macromolecule in order to establish important functional sites. We concentrate on the leading reaction of formaldehyde with free bases: hydroxymethylation of cytosine amino groups. Our results show that in B-DNA, cytosine amino groups are totally inaccessible for the formaldehyde attack. Then, we explore the effect of recently discovered transient flipping of Watson–Crick (WC) pairs into Hoogsteen (HG) pairs (HG breathing). Our results show that the HG base pair formation dramatically affects the accessibility for formaldehyde of the cytosine-aminonitrogens within WC-base pairs adjacent to HG-base pairs. The extensive literature on DNA interaction with formaldehyde is analysed in light of the new findings. The obtained data emphasize the significance of DNA HG breathing.