Intercalators. 1. Nature of stacking interactions between intercalators (ethidium, daunomycin, ellipticine, and 4',6-diaminide-2-phenylindole) and DNA base pairs. Ab initio quantum chemical, density functional theory, and empirical potential study.

Properties of isolated intercalators (ethidium (E), daunomycin (D), ellipticine (EL), and 4,6'-diaminide-2-phenylindole (DAPI)) and their stacking interactions with adenine...thymine (AT) and guanine...cytosine (GC) nucleic acid base pairs were investigated by means of a nonempirical correlated ab initio method. All intercalators exhibit large charge delocalization, and none of them (including the DAPI dication) exhibits a site with dominant charge. All intercalators have large polarizability and are good electron acceptors, while base pairs are good electron donors. MP2/6-31G*(0.25) stabilization energies of intercalator...base pair complexes are large (E...AT, 22.4 kcal/mol; D...GC, 17.8 kcal/mol; EL...GC, 18.2 kcal/mol; DAPI...GC, 21.1 kcal/mol) and are well reproduced by modified AMBER potential (van der Waals radii of intercalator atoms are enlarged and their energy depths are increased). Standard AMBER potential underestimates binding, especially for DAPI-containing complexes. Because the DAPI dication is the best electron acceptor (among all intercalators studied), this difference is explained by the importance of the charge-transfer term, which is not included in the AMBER potential. For the neutral EL molecule, the standard AMBER force field provides correct results. The Hartree-Fock and DFT/B3LYP methods, not covering the dispersion energy, fail completely to reveal any energy minimum at the potential energy curve of the E...AT complex, and these methods thus cannot be recommended for a study of intercalation process. On the other hand, an approximate version of the DFT method, which was extended to cover London dispersion energy, yields for all complexes very good stabilization energies that are well comparable with referenced ab initio data. Besides the vertical dependence of the interaction, an energy twist dependence of the interaction energy was also investigated by a reference correlated ab initio method and empirical potentials. It is concluded that, despite the cationic (E +1, D +1, DAPI +2) or polar (EL) character of the intercalators investigated, it is the dispersion energy which predominantly contributes to the stability of intercalator...base pair complexes. Any procedure which does not cover dispersion energy is thus not suitable for studying the process of intercalation.