| Abstract
| - The anticancer drug anthramycin inhibits replication and transcription processes by covalently binding toDNA. Here, we use molecular simulations to investigate the interaction between this ligand and thedodecanucleotide d[GCCAACGTTGGC]2. We start from the X-ray structure of the adduct anthramycin-d[CCAACGTTG*G]2, in which the drug binds covalently to guanine. We focus on the noncovalent complexesbetween the oligonucleotide and the anhydro and hydroxy forms of the drug. Molecular dynamics (MD)simulations show that only the hydroxy form lies in front of the reactive center for the whole simulation(∼20 ns), while the anhydro form moves inside the minor groove to the nearest base pair after ∼10 ns. Thissliding process is associated to both energetic and structural relaxations of the complex. The accuracy of ourcomputational setup is established by performing MD simulations of the covalent adduct and of a 14-mercomplexed with anhydro-anthramycin. The MD simulations are complemented by hybrid Car−Parrinelloquantum mechanics/molecular mechanics (QM/MM) simulations. These show that in the noncovalentcomplexes the electric field due to DNA polarizes the hydroxy and, even more, the anhydro form of the drugas to favor a nucleophilic attack by the alkylating guanine. This suggests that the binding process may becharacterized by a multistep pathway, catalyzed by the electric field of DNA.
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