title: Multistep drug intercalation: molecular dynamics and free energy studies of the binding of daunomycin to DNA.
abstract: Atomic-scale molecular dynamics and free energy calculations in explicit aqueous solvent are used to study the complex mechanism by which a molecule can intercalate between successive base pairs of the DNA double helix. We have analyzed the intercalation pathway for the anticancer drug daunomycin using two different methods: metadynamics and umbrella sampling. The resulting free energy pathways are found to be consistent with one another and point, within an equilibrium free energy context, to a three-step process. Daunomycin initially binds in the minor groove of DNA. An activated step then leads to rotation of the drug, coupled with DNA deformation that opens a wedge between the base pairs, bends DNA toward the major groove, and forms a metastable intermediate that resembles structures seen within the interfaces between DNA and minor-groove-binding proteins. Finally, crossing a small free energy barrier leads to further rotation of daunomycin and full intercalation of the drug, reestablishing stacking with the flanking base pairs and straightening the double helix.
authors.affiliation: Bioinformatics: Structures and Interactions, Bases Moléculaires et Structurales des Systèmes Infectieux, Univ. Lyon I/CNRS UMR, IBCP, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Wilhelm
authors.forename: Arnab
authors.initials: A
authors.lastname: Mukherjee
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bouvier
authors.forename: Krystyna
authors.initials: K
authors.lastname: Zakrzewska
authors.forename: James T
authors.initials: JT
authors.lastname: Hynes
authors.forename: Richard
authors.initials: R
authors.lastname: Lavery
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D003630:Daunorubicin / Q000494:pharmacology*; D007364:Intercalating Agents / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics
chemical_list: D000903:Antibiotics, Antineoplastic; D007364:Intercalating Agents; D004247:DNA; D003630:Daunorubicin