期刊
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
卷 38, 期 -, 页码 279-289出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jmgm.2012.05.006
关键词
Anti-cancer drug; Intercalation process; Molecular dynamics
类别
资金
- National Science Foundation of China [30870474]
The intercalation mode between doxorubicin (an anticancer drug) and two 6-base-pair DNA model fragments (d(CGATCG)(2) and d(CGTACG)(2)) has been well studied by X-ray crystallography and NMR experimental methods. Yet, the detailed intercalation pathway at molecular level remains elusive. In this study, we conducted molecular dynamics binding simulations of these two systems using AMBER DNA (parmbsc0) and drug (GAFF) force fields starting from the unbound state. We observed outside binding (minor groove binding or end-binding) in all six independent binding simulations (three for each DNA fragment), followed by the complete intercalation of a drug molecule in two simulations (one for each DNA fragment). First, our data directly supported that the minor groove binding is the dominant pre-intercalation step. Second, we observed that the opening and flipping of a local base pair (A3-T10 for d(CGATCG)(2) and C1-G12 for d(CGTACG)(2)) in the two intercalation trajectories. This locally cooperative flipping-intercalation mechanism was different from the previously proposed rise-insertion mechanism by which the distance between two neighboring intact base pairs increases to create a space for the drug insertion. Third, our simulations provided the first set of data to support the applicability of the AMBER DNA and drug force fields in drug-DNA atomistic binding simulations. Implications on the kinetics pathway and drug action are also discussed. (C) 2012 Elsevier Inc. All rights reserved.
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