We used molecular dynamics simulations to investigate interactions between DNA and three antineoplastic drugs from the anthracycline family, viz. daunomycin, doxorubicin and idarubicin. This encompassed three important aspects of DNA/drug interactions, viz. conformational perturbations, dynamics and energetics.
First, we investigated the structural perturbations caused by intercalation of the drugs into DNA. We found, using the software PyralleX which simulates X-ray diffraction patterns, that the DNA tends to change into an intermediary conformation between canonical forms. Daunomycin, among the three drugs, caused the greatest conformational shift in the DNA. Structural perturbations were shared with the base pairs adjacent to the intercalation sites.
Second, we studied the effects of groove-binding on the supercoiling behaviour of closed-circular DNA using the coarse-grained force field SIRAH. In the case without drugs, we saw an accelerating upward trend in the supercoiling rate with the salinity of the solution. However, with the drugs, supercoiling was found to retard in hypernatremic environments. Anthracyclines were found to form multilayer complex systems within themselves, which were capable of bridging across two segments of DNA and stabilising the DNA structure.
Third, we calculated the free energy changes associated with the intercalation of anthracyclines into DNA, using hybrid coarse-grained / all-atom models for simulation and the novel "extended-system adaptive biasing force" method for analysis. The free energy changes of intercalation of daunomycin and doxorubicin were calculated theoretically to be (-7.27 +/- 0.23) kcal/mol and (-8.61 +/- 0.33) kcal/mol respectively, which are in close agreement with previous experimental data. It was found that the calculated free energy change of idarubicin’s intercalation is (-7.75 +/- 0.17) kcal/mol, i.e. between those of the previous two drugs. This work has demonstrated a new way of evaluating free energy changes of interactions, which could help in speeding up time-consuming drug discovery processes.
