Binding of Anthracyclines Within DNA–Topoisomerase ΙΙ Cleavage Complexes: Thermodynamics and Interactions

All-atom molecular dynamics simulations of anthracycline–DNA–topoisomerase II (TOPII) cleavage complexes are undertaken in an aqueous environment, with particular emphasis on their thermodynamic description, using the double-decoupling method. Both the TOPIIα and TOPIIβ isoforms are considered herein, with doxorubicin and berubicin, two TOPII poisons, as the anthracyclines of interest. From a thermodynamic point of view, we find that all complexes investigated exhibit more negative standard binding Gibbs energies than berubicin–DNA intercalation complexes, showing that the presence of TOPIIα or TOPIIβ further stabilizes the complexes. The berubicin–DNA–TOPIIα complex exhibits the most negative standard binding Gibbs energy. Therefore, berubicin shows a preference for TOPIIα over TOPIIβ; the former is highly expressed in proliferating cells, including cancer cells, whereas the latter is expressed ubiquitously. From a nanoscopic point of view, our rigorous in silico approach sheds light on the interactions of the two anthracyclines with both DNA and TOPII and on how they contribute to the hindering of religation. Moreover, this study provides a detailed comparison between doxorubicin and berubicin in terms of relevant properties, such as contact numbers, hydrogen bonds, selected distances, and solvent-accessible surface areas.