Toward an understanding of the drug-DNA recognition mechanism. Hydrogen-bond strength in netropsin-DNA complexes

An ab initio quantum mechanical study of the binding of basic minor-groove drugs to DNA has been undertaken considering three interacting model systems, two concerning hydrogen bonds between amide moieties and one involving an interaction with a charged group. These are thymine ... formamide, thymine ... N-methylacetamide, and thymine ... thyleneiminium. The effect of the solvent on the interaction energy has been explored by using a self-consistent reaction field (SCRF) method based on the high-level Miertus-Scrocco-Tomasi algorithm. Furthermore, we have made a comparison of the intermolecular geometries of drug-DNA interactions by extracting information from the Nucleic Acid Data Base. The results indicate that interactions involving a charged group are about 5 times stronger than hydrogen bonds between noncharged groups in a gas-phase environment. However, both types of interactions are greatly modulated by the solvent. Thus, whereas a hydrogen bond between noncharged groups is clearly a hydrophobic interaction, the strong polarization effect induced by the charged group would eliminate the unfavorable effect of the solvent if a small variation of the intermolecular geometry is considered. These results suggest that interactions involving charged groups play a crucial role in the drug-DNA recognition and binding mechanism.