title: Molecular flexibility in ab initio drug docking to DNA: binding-site and binding-mode transitions in all-atom Monte Carlo simulations.
abstract: The dynamics of biological processes depend on the structure and flexibility of the interacting molecules. In particular, the conformational diversity of DNA allows for large deformations upon binding. Drug-DNA interactions are of high pharmaceutical interest since the mode of action of anticancer, antiviral, antibacterial and other drugs is directly associated with their binding to DNA. A reliable prediction of drug-DNA binding at the atomic level by molecular docking methods provides the basis for the design of new drug compounds. Here, we propose a novel Monte Carlo (MC) algorithm for drug-DNA docking that accounts for the molecular flexibility of both constituents and samples the docking geometry without any prior binding-site selection. The binding of the antimalarial drug methylene blue at the DNA minor groove with a preference of binding to AT-rich over GC-rich base sequences is obtained in MC simulations in accordance with experimental data. In addition, the transition between two drug-DNA-binding modes, intercalation and minor-groove binding, has been achieved in dependence on the DNA base sequence. The reliable ab initio prediction of drug-DNA binding achieved by our new MC docking algorithm is an important step towards a realistic description of the structure and dynamics of molecular recognition in biological systems.
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel. mail@remo-rohs.de
authors.forename: Remo
authors.initials: R
authors.lastname: Rohs
authors.forename: Itai
authors.initials: I
authors.lastname: Bloch
authors.forename: Heinz
authors.initials: H
authors.lastname: Sklenar
authors.forename: Zippora
authors.initials: Z
authors.lastname: Shakked
mesh_terms: D000465:Algorithms; D000962:Antimalarials / Q000737:chemistry; D001665:Binding Sites; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry*; D015195:Drug Design; D008024:Ligands; D008751:Methylene Blue / Q000737:chemistry; D008958:Models, Molecular; D009010:Monte Carlo Method; D009690:Nucleic Acid Conformation
chemical_list: D000962:Antimalarials; D008024:Ligands; D004247:DNA; D008751:Methylene Blue