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Unfolding and Conformational Variations of ThrombinBinding DNA Aptamers: Synthesis, Circular Dichroism and Molecular Dynamics Simulations
Sun, Lidan1; Jin, Hongwei1; Zhao, Xiaoyang2; Liu, Zhenming1; Guan, Yifu2; Yang, Zhenjun1; Zhang, Liangren1; Zhang, Lihe1
关键词G-quadruplexes molecular dynamics nucleosides simulations thrombin-binding DNA aptamers
刊名CHEMMEDCHEM
2014-05-01
DOI10.1002/cmdc.201300564
9期:5页:993-1001
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Chemistry, Medicinal ; Pharmacology & Pharmacy
资助者National S&amp ; T Major Project Foundation of China ; National Natural Science Foundation of China ; Ministry of Science and Technology of China ; National S&amp ; T Major Project Foundation of China ; National Natural Science Foundation of China ; Ministry of Science and Technology of China
研究领域[WOS]Pharmacology & Pharmacy
关键词[WOS]G-QUADRUPLEX STRUCTURES ; BINDING APTAMER ; 4-STRANDED DNA ; NUCLEIC-ACID ; STABILITY ; D(GGTTGGTGTGGTTGG) ; COMPLEXES ; SEQUENCE ; GROWTH
英文摘要

Thrombin-binding DNA aptamer (TBA), with a consensus 15-base sequence: d(GGTTGGTGTGGTTGG), can fold into an antiparallel unimolecular G-quadruplex structure that is necessary for its interaction with thrombin. For the first time, using steered molecular dynamics (SMD) simulations, we have successfully simulated the unfolding process of native TBA G-quadruplex. The unfolding pathway proposed is in agreement with previously reported experimental NMR data. Moreover, the critical intermediate structure in the unfolding pathway, predicted by the NMR results, was identified. The structural characteristics of several TBA oligonucleotides modified with locked nucleoside (LNA) or 2-O-methyl-nucleoside (MNA) at different positions and number were also investigated by CD spectroscopy. An oligonucleotide substituted with either LNA or MNA at position2 folds into a native-like G-quadruplex, while doubly substituted derivatives of TBA where LNA or MNA is incorporated at positions11 and14 are no longer able to form a G-quadruplex. Starting from the same initial intermediate structure, we successfully overcame sampling limitations, and simulated the large conformational variations in structures of native TBA and modified TBAs by classic MD. Analysis of the models showed that inversion of the glycosyl orientation at position14 contributes significantly to the disruption of G-quadruplex formation in both of the di-substituted modified TBA systems. Our calculations provide a simple and reliable theoretical model that can be used to investigate and predict the effects of the modifications of an oligonucleotide on the resultant G-quadruplex structure. In addition, the computational protocol described can also be applied for other G-quadruplex systems.

语种英语
所属项目编号2011ZX09102-001-17 ; 91213302 ; 2012CB720604
资助者National S&amp ; T Major Project Foundation of China ; National Natural Science Foundation of China ; Ministry of Science and Technology of China ; National S&amp ; T Major Project Foundation of China ; National Natural Science Foundation of China ; Ministry of Science and Technology of China
WOS记录号WOS:000335001700014
引用统计
被引频次:6[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/60952
专题北京大学药学院
作者单位1.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
2.China Med Univ, Dept Biochem & Mol Biol, Key Lab Med Cell Biol, Minist Educ, Shenyang 110013, Liaoning, Peoples R China
推荐引用方式
GB/T 7714
Sun, Lidan,Jin, Hongwei,Zhao, Xiaoyang,et al. Unfolding and Conformational Variations of ThrombinBinding DNA Aptamers: Synthesis, Circular Dichroism and Molecular Dynamics Simulations[J]. CHEMMEDCHEM,2014,9(5):993-1001.
APA Sun, Lidan.,Jin, Hongwei.,Zhao, Xiaoyang.,Liu, Zhenming.,Guan, Yifu.,...&Zhang, Lihe.(2014).Unfolding and Conformational Variations of ThrombinBinding DNA Aptamers: Synthesis, Circular Dichroism and Molecular Dynamics Simulations.CHEMMEDCHEM,9(5),993-1001.
MLA Sun, Lidan,et al."Unfolding and Conformational Variations of ThrombinBinding DNA Aptamers: Synthesis, Circular Dichroism and Molecular Dynamics Simulations".CHEMMEDCHEM 9.5(2014):993-1001.
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