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提高我们对RNA稳定性，折叠和动态的理解。由于RNA分子的生物学功能主要取决于其形状，我们认为实现此目标将需要开发（a）（a）特征RNA形状的几何形状和稳定性的新方法，（b）表征在RNA折叠上出现的中间体的新技术，以及（c）描述RNA序列空间和结构序列之间的新方法。该提案成功的关键在于其在NIH国家生物医学计算中心“基于物理学的生物结构模拟”中的协作整合，由斯坦福大学主持，由Russ Altman教授领导。斯坦福中心的几个PI的专业知识，包括Altman，Levitt和Pande教授，在RNA动力学领域以及他们开发的SIMTK库中许多结构生物学的计算方法的可用性将是成功的。特别是，我们将基于我们最初用于研究蛋白质溶剂的成功方法，开发快速，准确和分析方法来测量RNA分子的几何特性来测量RNA分子的几何特性。我们对计算表面可及性以及将这种几何测量与实验数据（例如羟基自由基足迹）相关的感兴趣。 （2）开发一种新的形式主义，用于计算RNA周围的静电场。我们建议使用广义的泊松托尼 - 洛格文方程来描述水在水中产生的静电场，基于对溶剂作为自由定向偶极子的组装的描述。 （3）在扭转和笛卡尔空间中使用正交正常模式来表征RNA动力学。我们特别有兴趣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。我们将应用为蛋白质序列设计开发的方法来测量RNA接受突变而不会失去其结构的能力。 （5）RNA结构的几何和物理特性的可视化。我们将将在斯坦福大学开发的龙卷风RNA可视化平台扩展到理论与生物学之间的有效接口。