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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. and Bloch, I. and 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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