Integrated Computational and Spectroscopic Analyses to unravel the Role of Cu(II) Coordination in Modulating Doxorubicin-DNA Binding

Abstract

Doxorubicin (DOX) is a clinically important anthracycline whose anticancer activity is closely associated with DNA binding. However, the structural basis by which metal coordination modulates DOX-DNA association remains poorly understood. Here, an integrated computational and spectroscopic approach was employed to elucidate the role of Cu(II)-coordination in modulating the structure of DOX and its DNA binding. DFT, molecular docking, and molecular dynamics simulations established a stable intercalative association of DOX with DNA. At the same time, DFT-based characterization of Cu(II)-DOX revealed coordination induced structural and electronic changes consistent with reduced conformational freedom and increased rigidity. This led to the hypothesis that Cu(II) coordination may favor an intercalation-compatible configuration of DOX. UV-Vis and competitive fluorescence studies experimentally supported Cu(II)-dependent modulation of DOX-DNA association, with UV-Vis analysis indicating a substantial tenfold increase in apparent DNA-binding affinity and fluorescence measurements confirming pronounced perturbation of DNA-associated ethidium bromide. Collectively, the findings establish a coherent relationship between Cu(II) coordination, DOX conformational modulation, and DNA recognition, highlighting metal coordination as a potential strategy for tuning the biomolecular interactions of anthracycline therapeutics.