Molecular electrostatic potentials: an effective tool for the elucidation of biochemical phenomena.

The electrostatic potential V(r) that is created in the space around a molecule by its nuclei and electrons (treated as static distributions of charge) is a very useful property for analyzing and predicting molecular reactive behavior. It is rigorously defined and can be determined experimentally as well as computationally. The potential has been particularly useful as an indicator of the sites or regions of a molecule to which an approaching electrophile is initially attracted, and it has also been applied successfully to the study of interactions that involve a certain optimum relative orientation of the reactants, such as between a drug and its cellular receptor. A variety of methods for calculating V(r) is available, at different levels of rigor. For large biologically active molecules, multipole expansions and superposition of potentials computed for subunits have been found to be effective. A large number of chemical and biochemical systems and processes have now been studied in terms of electrostatic potentials. Three examples of such applications are surveyed in this paper. These deal with: (a) reactive properties of nucleic acids, including their component bases; (b) biological recognition processes, including drug-receptors and enzyme-substrate interactions; and (c) chemical carcinogenesis, referring specifically to the polycyclic aromatic hydrocarbons and halogenated olefins and their epoxides. For each of these areas, examples of the use of electrostatic potentials in elucidating structure-activity patterns are given.

Relationships between the electrostatic potential, epoxide hydrase inhibition and carcinogenicity for some hydrocarbon and halogenated hydrocarbon epoxides.

For a group of nine hydrocarbon and halogenated hydrocarbon epoxides, there is shown to be a good correlation between their abilities to inhibit epoxide hydrase and the quantity Vmin /Es, where Vmin is the most negative value of the molecule's electrostatic potential in the neighborhood of the epoxide oxygen and Es is a factor that takes account of steric effects. It is also demonstrated that carcinogenicity, for thirteen epoxides, appears to be associated with Vmin having a relatively large negative value. On this basis, several other epoxides are predicted to be carcinogenic. The electrostatic potentials used in developing these relationships have been computed by an ab initio self-consistent-field molecular orbital procedure, using optimized molecular geometries.