jp063155n_si_001.pdf (198.28 kB)
Anthramycin−DNA Binding Explored by Molecular Simulations
journal contribution
posted on 2006-12-07, 00:00 authored by Attilio V. Vargiu, Paolo Ruggerone, Alessandra Magistrato, Paolo CarloniThe anticancer drug anthramycin inhibits replication and transcription processes by covalently binding to
DNA. Here, we use molecular simulations to investigate the interaction between this ligand and the
dodecanucleotide 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 complexes
between 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. This
sliding process is associated to both energetic and structural relaxations of the complex. The accuracy of our
computational setup is established by performing MD simulations of the covalent adduct and of a 14-mer
complexed with anhydro-anthramycin. The MD simulations are complemented by hybrid Car−Parrinello
quantum mechanics/molecular mechanics (QM/MM) simulations. These show that in the noncovalent
complexes the electric field due to DNA polarizes the hydroxy and, even more, the anhydro form of the drug
as to favor a nucleophilic attack by the alkylating guanine. This suggests that the binding process may be
characterized by a multistep pathway, catalyzed by the electric field of DNA.