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：
8244581
负责人：
Tamar Schlick
金额：
$ 40万
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8244581
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 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. PUBLIC HEALTH RELEVANCE: No description provided.

描述（由申请人提供）：RNA分子是与许多基本生物学作用有关的重要细胞成分。由于RNA的结构特征与其生物学功能密切相关，因此对从序列预测RNA结构非常感兴趣。拟议的研究既解决RNA结构预测 - 使用图理论和统计工具的层次建模方法的开发以及RNA设计 - 工程荧光核糖开关，可以“感知”转录终止，从而提供了研究过程的研究。所提出的方法需要开发新的数学和统计/计算机科学工具，以在3D中有效地采样RNA图对象，以提供初始的，粗略的采样级别，并用于开发基于系统结构的统计方法，以使用数据挖掘工具来评分RNA构象。基于已知结构的RNA结基序的广泛分析将用于开发单独的局部和全球统计潜力，以预测局部几何学取向以及全球远程相互作用。这些RNA模型和相关电位将在以下层次设计中的三个相关折叠阶段进行组合和仔细测试：（1）探索RNA的结构构象空间，使用代表RNA 2D结构中嵌入的RNA 2D结构的MC采样，嵌入了3D型结构中，这些构造具有与RNA相同的统计潜能中嵌入的RNA 2D结构。（2）使用具有高级统计潜力的粗粒粒度的每核苷酸模型提高预测准确性，以指导3D组装；（3）使用动力学模拟在具有力场电位的完整原子模型上完善最佳候选者。经过仔细的分析，然后对新数学工具进行开发和测试，计划的每个阶段将被完善，以最终整合组件。通过将荧光适体的已知元素与控制基因表达的核糖开关的基于配体的构型重排，将追求荧光核糖开关的新设计应用。公共卫生相关性：没有提供描述。