Cooperativity effect of the π⋯π interaction between drug and DNA on intercalative binding induced by H-bonds: a QM/QTAIM investigation of the curcumin⋯adenine⋯H2O model system

Abstract

In order to reveal the nature of intercalative binding of drug to DNA, the cooperativity effect of the π⋯π interaction was investigated in the curcumin⋯adenine⋯H₂O model system by applying a combined QM and QTAIM computational approach. The H-bonds between the electron-donating group of curcumin and adenine induce the formation of the π⋯π stacking. The introduction of H₂O weakens the H-bonding and π⋯π interactions, leading to an anti-cooperativity effect, as is confirmed by the AIM (atoms in molecules) and RDG (reduced density gradient) analysis. Thus, it can be inferred that the anti-cooperative effect is the main driving force for the intercalative binding of drug to DNA bases, which is in agreement with many experimental phenomena. Therefore, the designed DNA-targeted intercalating drugs should possess not only hydrophobic moieties, but also strong electron-donating groups bound to the DNA bases with H-bonds, which can slow the variation rates of the strengths of the H-bonding and π⋯π interactions between drug and DNA bases in the anti-cooperative process, leading to the intercalation formation. The enthalpy change is the major factor driving the positive thermodynamic cooperativity.