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Modeling RNA Tertiary Structure Folding by a Hierarchical Framework

通过分层框架模拟 RNA 三级结构折叠

基本信息

批准号：
8689107
负责人：
Tamar Schlick
金额：
$ 36.74万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-09 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8689107
关键词：
Address Algorithms Bioinformatics Biological Biological Process Cereals Classification Cluster Analysis Complex DNA Sequence Rearrangement Data Set Development Elements Engineering Family Free Energy Gene Expression Genetic Transcription Geometry Graph Helix-Turn-Helix Motifs Imagery Indium Ligands Methods Modeling Molecular Conformation Mutation Nucleotides Phase Potential Energy Process Protocols documentation RNA RNA Conformation RNA Folding RNA Stability RNA analysis Reporter Research Research Personnel Resolution Role Sampling Sorting - Cell Movement Staging Structure Testing Thermodynamics Thiamine Pyrophosphate Trees Work aptamer arm base computer science data mining design engineering design flexibility forest improved in vivo innovation interest molecular dynamics novel novel strategies preference programs restraint sensor simulation statistics theories three dimensional structure tool transcription termination

项目摘要

DESCRIPTION (provided by applicant): RNA molecules are important cellular components involved in many fundamental biological roles. Because the structural features of RNA are intimately connected to their biological function, there is great interest in predicting RNA structure from sequence. The proposed research addresses both RNA structure prediction - development of a hierarchical modeling approach using graph theory and statistical tools, and RNA design - engineering fluorescent riboswitches that can "sense" transcription termination, offering researches visualization of the process in vivo. The proposed approach requires development of new mathematical and statistical/computer science tools for sampling RNA graph objects efficiently in 3D - to provide an initial, coarse level of sampling - and for developing systematically structure-based statistical approaches to score RNA conformations using data-mining tools. Extensive analysis of RNA junction motifs based on known structures will be used to develop separate local and global statistical potentials to predict both local geometric orientations, as well as global long-range interactions. These RNA models and associated potentials will be combined and carefully tested in three inter-related stages of folding in the following hierarchical design: (1) Explore RNA's structural conformation space coarsely using MC sampling on tree graphs that represent RNA 2D structures embedded in 3D lattices with statistical potentials that select RNA-like conformations; (2) Improve prediction accuracy using a coarse-grained three-bead-per-nucleotide model with a higher-level statistical potential to guide 3D assembly; and (3) Refine the best candidates using dynamics simulations on full atomistic models with force-field potentials. After careful analysis followed by development and testing of the new mathematical tools, each stage of the plan will be refined to finally integrate the components. New design applications for fluorescent riboswitches will be pursued, by marrying known elements of fluorescent aptamers with ligand-based configurational rearrangements of riboswitches that control gene expression.

描述（由申请人提供）：RNA分子是参与许多基本生物学作用的重要细胞组分。由于RNA的结构特征与其生物学功能密切相关，因此从序列中预测RNA结构具有很大的意义。拟议的研究解决了RNA结构预测-使用图论和统计工具开发分层建模方法，以及RNA设计-工程荧光核糖开关，可以“感知”转录终止，为研究人员提供体内过程的可视化。所提出的方法需要开发新的数学和统计/计算机科学工具，用于在3D中有效地对RNA图形对象进行采样，以提供初始的、粗略的采样水平，并用于开发系统的基于结构的统计方法，以使用数据挖掘工具对RNA构象进行评分。基于已知结构的RNA连接基序的广泛分析将用于开发单独的局部和全局统计潜力，以预测局部几何方向以及全局长程相互作用。这些RNA模型和相关的势将在以下分层设计中的三个相互关联的折叠阶段中被组合和仔细测试：（1）使用树图上的MC采样粗略地探索RNA的结构构象空间，该树图表示嵌入在具有选择RNA样构象的统计势的3D晶格中的RNA 2D结构;（2）使用粗粒度的每个核苷酸三个珠子的模型提高预测准确性，该模型具有更高级别的统计潜力来指导3D组装;以及（3）使用具有力场势的全原子模型的动力学模拟来优化最佳候选者。经过仔细分析，然后开发和测试新的数学工具，该计划的每个阶段将被细化，最终整合的组成部分。荧光核糖开关的新设计应用将被追求，通过结合已知的荧光适体元件与控制基因表达的核糖开关的基于配体的构型重排。