Cobaltabis(dicarbollide)\nInteraction with DNA Resolved\nat the Atomic Scale

Boron neutron capture therapy represents a promising\navenue for\ncancer treatment that requires nontoxic drugs with a high boron content\nefficiently distributed into cancerous cells. The metallacarborane <i>o</i>-cobaltabis(dicarbollide) ([COSAN]<sup>−</sup>)\nfulfills these requirements and constitutes an attractive candidate.\nNevertheless, the interaction of this promising drug with nucleic\nacids, the assumed target of the biological damage, is poorly understood\nsince contradictory results are reported in the literature. This work\nestablishes the DNA/[COSAN]<sup>−</sup> interaction strength,\nmechanism, and time scale at the atomistic level by using a combination\nof microsecond-molecular dynamics and hybrid quantum mechanics/molecular\nmechanics simulations and by quantifying the absolute binding free\nenergy. Results show that the DNA/[COSAN]<sup>−</sup> interaction\nis highly dependent on the ionic strength of the medium. A relatively\nweak DNA major groove binding (Δ<i>G</i><sub>bind</sub>= −2.49 kcal/mol) driven mostly by dihydrogen B–H···H–N\nbonding is observed in the simulations only at a high NaCl concentration,\nwhereas DNA intercalation mode is deemed highly unlikely.