Intercalation Favors DNA Covalent Photobinding in Photoresponsive Dual PDT/PCT Bimetallic Assemblies

The local treatment of solid tumors through photoactivated therapies demands the development of alternative strategies independent of oxygen levels, which are often very low in cancerous tissues. In this regard, the combination of an efficient reactive oxygen species (ROS) photogenerator with a drug that covalently targets DNA represents a valuable approach due to the in situ combination of type I/II photodynamic reactions with the covalent blockage of the DNA biological function. In this context, the theoretical framework of the chemical events that cause the observed phototoxicity is far from being fully understood, especially the dynamic factors, timescales, and environmental effects. This work sheds light on the molecular basis of these events by studying the DNA photoreactivity of a Ru(II)/Os(II) and a Pt(II) bimetallic assembly via microsecond molecular dynamics and multiscale biased quantum mechanics/molecular mechanics (QM/MM) MD simulations. Analysis of the DNA interaction modes reveals persistent major/minor groove interactions of the photosensitizer and a thermodynamically favored DNA intercalation. On the other hand, the free energy landscapes reveal kinetically fast (energy barriers ca. 6 kcal·mol–1) ligand exchange reactions between the N7 position of guanine and the platinum center in the triplet excited state, clearly highlighting the role of light in accelerating the chemical process. Additional analyses suggest that DNA intercalation, often associated with high cellular toxicity, could instead be seen as an opportunity to increase phototoxicity indexes by reducing the DNA conformational space available for photoreactions and improving absorption properties.