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题名: Mechanism of MicroRNA-Target Interaction: Molecular Dynamics Simulations and Thermodynamics Analysis
作者: Wang, Yonghua1;  Li, Yan2;  Ma, Zhi1;  Yang, Wei1;  Ai, Chunzhi3
刊名: PLOS COMPUTATIONAL BIOLOGY
发表日期: 2010-07-01
DOI: 10.1371/journal.pcbi.1000866
卷: 6, 期:7
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Biochemical Research Methods ;  Mathematical & Computational Biology
研究领域[WOS]: Biochemistry & Molecular Biology ;  Mathematical & Computational Biology
英文摘要: MicroRNAs (miRNAs) are endogenously produced similar to 21-nt riboregulators that associate with Argonaute (Ago) proteins to direct mRNA cleavage or repress the translation of complementary RNAs. Capturing the molecular mechanisms of miRNA interacting with its target will not only reinforce the understanding of underlying RNA interference but also fuel the design of more effective small-interfering RNA strands. To address this, in the present work the RNA-bound (Ago-miRNA, Ago-miRNA-target) and RNA-free Ago forms were analyzed by performing both molecular dynamics simulations and thermodynamic analysis. Based on the principal component analysis results of the simulation trajectories as well as the correlation analysis in fluctuations of residues, we discover that: 1) three important (PAZ, Mid and PIWI) domains exist in Argonaute which define the global dynamics of the protein; 2) the interdomain correlated movements are so crucial for the interaction of Ago-RNAs that they not only facilitate the relaxation of the interactions between residues surrounding the RNA binding channel but also induce certain conformational changes; and 3) it is just these conformational changes that expand the cavity of the active site and open putative pathways for both the substrate uptake and product release. In addition, by thermodynamic analysis we also discover that for both the guide RNA 5'-end recognition and the facilitated site-specific cleavage of the target, the presence of two metal ions (of Mg(2+)) plays a predominant role, and this conclusion is consistent with the observed enzyme catalytic cleavage activity in the ternary complex (Ago-miRNA-mRNA). Our results find that it is the set of arginine amino acids concentrated in the nucleotide-binding channel in Ago, instead of the conventionally-deemed seed base-paring, that makes greater contributions in stabilizing the binding of the nucleic acids to Ago.
关键词[WOS]: ARGONAUTE SILENCING COMPLEX ;  PAZ DOMAIN ;  CRYSTAL-STRUCTURE ;  SOLVENT MODELS ;  FREE-ENERGIES ;  ANIMAL DEVELOPMENT ;  GENERALIZED-BORN ;  SLICER ACTIVITY ;  RNA-BINDING ;  HUMAN RISC
语种: 英语
WOS记录号: WOS:000280528300035
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/142007
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.NW A&F Univ, Ctr Bioinformat, Yangling, Shaanxi, Peoples R China
2.Dalian Univ Technol, Sch Chem Engn, Dalian, Liaoning, Peoples R China
3.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian, Liaoning, Peoples R China

Recommended Citation:
Wang, Yonghua,Li, Yan,Ma, Zhi,et al. Mechanism of MicroRNA-Target Interaction: Molecular Dynamics Simulations and Thermodynamics Analysis[J]. PLOS COMPUTATIONAL BIOLOGY,2010,6(7).
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