Unravelling the binding affinity and selectivity of molybdenum(II) phenanthroline complexes with DNA G-quadruplexes by using linear-scaling DFT studies. The important role of ancillary ligands.

We have used near linear-scaling density functional theory (LS-DFT) methods including dispersion, for the first time, to study the interaction of two isomers, equatorial (Eq) and axial (Ax), of the [Mo(η-CH)Br(CO)(phen)] metal complex with the DNA G-quadruplexes (GQ) to gain insight into its cytotoxicity. The LMKLL/DZDP level of calculation, which includes van der Waals contributions, with the SIESTA software was used to treat by means of first-principles computations the whole biological studied model system with ∼1000 atoms. Computed formation energies point to systems containing the Ax isomer as the most stable although the nearest system in energy containing the Eq isomer is only 7.5 kcal mol above. On the other hand, the energy decomposition analysis (EDA) favours interaction energies for the systems containing the Eq isomer. However, when solvent effects are taken into account the systems containing the Ax isomer are again the most stable. This Ax isomer was found interacting by means of end-stacking with the GQ and surprisingly totally inside the non-canonical secondary structure, where all the ligands of the metal complex produce several weak interactions with the DNA structure. On the other hand, the Eq isomer prefers to interact from outside by means of intercalation in which the ancillary ligands also have some role in the interaction. Such features and comparison with the results regarding the interaction of the [Mo(η-CH)Br(CO)(phen)] metal complex with duplex DNA suggest that the [Mo(η-CH)Br(CO)(phen)] would have a higher affinity and eventual selectivity for non-canonical DNA GQ structures.