Geometric-based and Physics-based Simulations of RNA Folding

RNA 折叠的基于几何和物理的模拟

• 批准号: 7595817
• 负责人: Patrice A Koehl
• 金额: $ 28.13万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595817
• 关键词: Amino Acid Sequence; Biochemical; Biological; Biological Process; Biology; Biomedical Computing; Cell physiology; Cells; Characteristics; Charge; Code; Communities; Complement; Computer software; Computing Methodologies; Data; Development; Electrostatics; Ensure; Equation; Evolution; Functional RNA; Genetic; Hydroxyl Radical; Imagery; Introns; Ions; Lead; Libraries; Ligands; Maps; Measures; Methods; Modeling; Molecular Conformation; Mutation; Paper; Pathway interactions; Peptide Sequence Determination; Physics; Property; Protein Dynamics; Proteins; Publishing; RNA; RNA Binding; RNA Folding; RNA Sequences; RNA Stability; Research Personnel; Shapes; Solvents; Structure; Surface; Techniques; Tetrahymena thermophila; Tornadoes; Torsion; Translations; United States National Institutes of Health; Universities; Visual; Water; Work; base; c new; catalyst; density; design; globular protein; insight; interest; novel strategies; physical property; programs; protein structure; research study; simulation; software development; structural biology; success; theories; tool

DESCRIPTION (provided by applicant): The main aim of this proposal is to advance our understanding of RNA stability, folding and dynamics. As the biological function of an RNA molecule mostly depends on its shape, we believe that achieving this aim will require the development of (a) new approaches to characterize the geometry and stability of RNA shapes, (b) new techniques to characterize intermediates that appear upon RNA folding, and (c) new methods to describe the map between RNA sequence space and structure space. The key to the success of this proposal lies in its collaborative integration within the NIH National Center for Biomedical Computing "Physics-based Simulation of Biological Structures", hosted at Stanford University, and lead by Prof. Russ Altman. The expertise of several Pis at the Stanford Center, including Profs Altman, Levitt and Pande, in the field of RNA dynamics as wells as the availability of many computational methods for structural biology in the SimTK library they have developed will prove invaluable for success. In particular, we will collaborate on the following specific aims: (1) Develop fast, accurate and analytic methods to measure geometric properties of RNA molecules, based on the successful methods we have originally developed for studying protein solvation. We are interested in particular in computing surface accessibility, and in correlating this geometric measure to experimental data such as hydroxyl radical footprinting. (2) Develop a new formalism for computing the electrostatic field around RNA. We propose to use a generalized Poisson-Boltzmann-Langevin equation to describe the electrostatic field generated by RNA in water, based on a description of the solvent as an assembly of freely orienting dipoles. (3) Use orthogonal normal modes in torsion and Cartesian space to characterize RNA dynamics. We are particularly interested in defining pathways between potential conformations of a RNA molecule using a combination of physical or elastic normal modes. (4) Describe the sequence space compatible with a RNA tertiary structure. We will apply the methods we have developed for protein sequence design to measure the ability of RNA to accept mutations without losing its structure. (5) Visualization of the geometric and physical properties of RNA structures. We will expand the ToRNADo RNA visualization platform developed at Stanford into an effective interface between theory and biology.

描述（由申请人提供）：该提案的主要目的是增进我们对 RNA 稳定性、折叠和动力学的理解。由于RNA分子的生物学功能主要取决于其形状，我们认为实现这一目标将需要开发（a）新方法来表征RNA形状的几何形状和稳定性，（b）新技术来表征出现的中间体RNA折叠，以及（c）描述RNA序列空间和结构空间之间图谱的新方法。该提案成功的关键在于其与 NIH 国家生物医学计算中心“基于物理的生物结构模拟”的协作整合，该中心由斯坦福大学主办，由 Russ Altman 教授领导。斯坦福中心的几位 Pi 教授，包括 Altman、Levitt 和 Pande 教授，在 RNA 动力学领域的专业知识以及他们开发的 SimTK 库中许多结构生物学计算方法的可用性，对于成功而言将是无价的。具体而言，我们将在以下具体目标上进行合作：（1）基于我们最初开发的用于研究蛋白质溶剂化的成功方法，开发快速、准确的分析方法来测量RNA分子的几何特性。我们特别感兴趣的是计算表面可及性，并将这种几何测量与实验数据（例如羟基自由基足迹）相关联。 (2) 开发一种计算 RNA 周围静电场的新形式。我们建议使用广义的 Poisson-Boltzmann-Langevin 方程来描述 RNA 在水中产生的静电场，基于将溶剂描述为自由定向偶极子的集合。 (3) 使用挠场和笛卡尔空间中的正交简正模态来表征 RNA 动力学。我们特别感兴趣的是使用物理或弹性正常模式的组合来定义 RNA 分子的潜在构象之间的途径。 (4) 描述与RNA三级结构兼容的序列空间。我们将应用我们开发的蛋白质序列设计方法来测量 RNA 接受突变而不丢失其结构的能力。 (5) RNA结构的几何和物理特性的可视化。我们将把斯坦福大学开发的 ToRNADo RNA 可视化平台扩展为理论和生物学之间的有效接口。