Binding modes of a flexible ruthenium polypyridyl complex to DNA†

Ruthenium(II) polypyridyl complexes are attractive binders to DNA. Modifying the hydrophobicity, shape, or size of the ancillary ligands around the central ruthenium atom can induce changes in the binding mode to the DNA double helix. In this paper, we investigate the binding modes of [Ru(2,2′-bipyridine)₂ (5-{4-[(pyren-1-yl)methyl]-1H-1,2,3-triazol-4-yl}-1,10-phenanthroline)]²⁺ (RuPy for short), a metal complex featuring a flexible pyrene moiety known for its intercalative properties. Classical molecular dynamics simulations are employed to gain insight into the non-covalent binding interactions of RuPy with two different 20 base pair DNA sequences, poly(dA)poly(dT) (AT) and poly(dC)poly(dG) (CG). In addition to examining the intercalation of the pyrene moiety from the major groove, the stability of RuPy–DNA adducts is investigated when the metal complex interacts externally with the DNA and with the major and minor groove pockets. The results indicate that external interaction and major groove binding are not stable, whereas intercalation consistently forms stable adducts. Minor groove binding showed less stability than intercalation and more variability, with some trajectories transitioning to intercalation, involving either the pyrene moiety or a bipyridine ligand. Pyrene intercalation, especially from the minor groove, was the most stable, while bipyridine intercalation was less favorable and associated with higher binding free energies.