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(η3- C3H5)Br(CO)2(phen)] metal complex with the DNA G-quadruplexes (GQ) to gain insight on its cytoxicity. 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 and the energy decomposition analysis (EDA) point to systems containing the Eq isomer as the most stable. However, when solvent effects are taken into account the systems containing the Ax isomer are 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 have also some role in the interaction. Nevertheless, some stable system was found for the Eq isomer in which the Br halogen atom was the main link through which the interaction is produced between the metal complex and DNA bases. For this case, the weak interactions produced by the ancillary ligands are very important, whereas no π − π stacking is found through the phen ligand. Such features and comparison with the results regarding the interaction of [Mo(η3-C3H5)Br(CO)2(phen)] metal complex with duplex DNA suggest that the [Mo(η3-C3H5)Br(CO)2(phen)] complex would have higher affinity and eventual selectivity for non-canonical DNA GQ structures.