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Early stage intercalation of doxorubicin to DNA fragments observed in molecular dynamics binding simulations
Lei, HX; Wang XF(王晓峰); Wang, XF; Wu, C
2012
发表期刊JOURNAL OF MOLECULAR GRAPHICS & MODELLING
卷号38页码:279-289
通讯作者[Lei, Hongxing ; Wang, Xiaofeng] Chinese Acad Sci, Beijing Inst Genom, CAS Key Lab Genome Sci & Informat, Beijing 100029, Peoples R China ; [Wang, Xiaofeng] Chinese Acad Sci, Inst High Energy Phys, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100049, Peoples R China ; [Wu, Chun] Univ Calif Santa Barbara, Dept Chem & Biochem, Santa Barbara, CA 93106 USA
文章类型Article
摘要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.
关键词Anti-cancer drug Intercalation process Molecular dynamics
学科领域Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology
研究领域[WOS]Biochemistry & Molecular Biology ; Computer Science ; Crystallography ; Mathematical & Computational Biology ; Biochemistry & Molecular Biology ; Computer Science ; Crystallography ; Mathematical & Computational Biology
DOI10.1016/j.jmgm.2012.05.006
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语种英语
研究领域[WOS]Biochemistry & Molecular Biology ; Computer Science ; Crystallography ; Mathematical & Computational Biology ; Biochemistry & Molecular Biology ; Computer Science ; Crystallography ; Mathematical & Computational Biology
WOS类目Biochemical Research Methods ; Biochemistry & Molecular Biology ; Computer Science, Interdisciplinary Applications ; Crystallography ; Mathematical & Computational Biology
WOS记录号WOS:000313392800028
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文献类型期刊论文
条目标识符http://ir.ihep.ac.cn/handle/311005/236868
专题多学科研究中心
作者单位中国科学院高能物理研究所
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Lei, HX,Wang XF,Wang, XF,et al. Early stage intercalation of doxorubicin to DNA fragments observed in molecular dynamics binding simulations[J]. JOURNAL OF MOLECULAR GRAPHICS & MODELLING,2012,38:279-289.
APA Lei, HX,王晓峰,Wang, XF,&Wu, C.(2012).Early stage intercalation of doxorubicin to DNA fragments observed in molecular dynamics binding simulations.JOURNAL OF MOLECULAR GRAPHICS & MODELLING,38,279-289.
MLA Lei, HX,et al."Early stage intercalation of doxorubicin to DNA fragments observed in molecular dynamics binding simulations".JOURNAL OF MOLECULAR GRAPHICS & MODELLING 38(2012):279-289.
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