Computational Studies on the Binding Preferences of Molybdenum(II) Phenanthroline Complexes with Duplex DNA. The Important Role of the Ancillary Ligands.

The interaction of two isomers, equatorial (Eq) and axial (Ax), of the [Mo(η-CH)Br(CO)(phen)] metal complex with DNA was studied by using large-scaling density functional theory methods including dispersion for the whole system, represented as a d(AGACGTCT) DNA octamer, to gain insight into its experimentally found cytotoxicity. Three different modes of interaction were considered: (1) minor groove (mg) binding, (2) intercalation through the major groove (MG), and (3) the apparently unexpected intercalation via the mg. Computed formation energies, energy decomposition analysis, solvation energies, and noncovalent interaction analysis explain the preference for Eq and Ax isomers of the complex for intercalation via the mg. π-π interactions of the phenanthroline (phen) flat ligand that appear in the intercalation mode and do not exist for the mg binding mode suggest the preference of [Mo(η-CH)Br(CO)(phen)] for intercalation. On the other hand, the role of the ancillary ligands is crucial for better interaction of the metal complex including phen than when the phen ligand alone is considered because of their additional interactions with base pairs (bps). The role of the ancillary ligands is enhanced when intercalation takes place through the mg because such ligands are able to interact not only with bps but also with the sugar and phosphate backbone, whereas for intercalation through the MG, the interaction of these ligands is only with bps. This feature explains the preference of [Mo(η-CH)Br(CO)(phen)] for intercalation via the mg in crystal structures. Finally, the solvation penalty is more important for intercalation through the mg than via the MG, which suggests a subtle mechanism involving weak interactions with solvent molecules to explain the selectivity for intercalation in solution to answer the MG versus mg question.