Cobaltabis(dicarbollide) Interaction with DNA Resolved at the Atomic Scale

Boron neutron capture therapy represents a promising avenue for cancer treatment that requires nontoxic drugs with a high boron content efficiently distributed into cancerous cells. The metallacarborane o-cobaltabis(dicarbollide) ([COSAN]^-) fulfills these requirements and constitutes an attractive candidate. Nevertheless, the interaction of this promising drug with nucleic acids, the assumed target of the biological damage, is poorly understood since contradictory results are reported in the literature. This work establishes the DNA/[COSAN]^- interaction strength, mechanism, and time scale at the atomistic level by using a combination of microsecond-molecular dynamics and hybrid quantum mechanics/molecular mechanics simulations and by quantifying the absolute binding free energy. Results show that the DNA/[COSAN]^- interaction is highly dependent on the ionic strength of the medium. A relatively weak DNA major groove binding (ΔG_bind= -2.49 kcal/mol) driven mostly by dihydrogen B-H···H-N bonding is observed in the simulations only at a high NaCl concentration, whereas DNA intercalation mode is deemed highly unlikely.