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Molecular flexibility in ab initio drug docking to DNA: binding-site and binding-mode transitions in all-atom Monte Carlo simulations

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Item Type:Article
Title:Molecular flexibility in ab initio drug docking to DNA: binding-site and binding-mode transitions in all-atom Monte Carlo simulations
Creators Name:Rohs, R., Bloch, I., Sklenar, H. and Shakked, Z.
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.
Keywords:Algorithms, Antimalarials, Binding Sites, Computer Simulation, DNA, Drug Design, Ligands, Methylene Blue, Molecular Models, Monte Carlo Method, Nucleic Acid Conformation
Source:Nucleic Acids Research
ISSN:0305-1048
Publisher:Oxford University Press
Volume:33
Number:22
Page Range:7048-7057
Date:13 December 2005
Official Publication:https://doi.org/10.1093/nar/gki1008
PubMed:View item in PubMed

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