RNA folding: from global structure to atomic detail

RNA折叠：从整体结构到原子细节

• 批准号: 8134861
• 负责人: Ron Elber
• 金额: $ 32.4万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134861
• 关键词: Agreement; Architecture; Awareness; Bacteriophages; Base Pairing; Binding; Biological Process; Biotechnology; Catalytic RNA; Cell physiology; Charge; Complex; Coupled; Coupling; Data; Development; Double-Stranded RNA; Educational process of instructing; Elements; Enzymes; Event; Fluorescence; Functional RNA; Gene Expression; Gene Expression Regulation; Goals; Hydroxyl Radical; Individual; Introns; Ions; Kinetics; Knowledge; Length; Link; Magnesium; Measures; Medicine; Messenger RNA; Methods; Modeling; Molecular Machines; Mono-S; Property; Proteins; RNA; RNA Folding; RNA Interference; Reaction; Reporting; Research Design; Ribosomes; Role; Sampling; Small RNA; Sodium Chloride; Spatial Distribution; Staging; Strontium; Structure; Switch Genes; Techniques; Testing; Therapeutic; Thermodynamics; Time; Transcript; Vertebral column; base; computerized tools; design; flexibility; meetings; planetary Atmosphere; protein folding; public health relevance; research study; self assembly; simulation; success; theories; time use; tool

DESCRIPTION (provided by applicant): In contrast with the earliest models suggesting that it functioned only as messenger, RNA is now known to participate in a myriad of essential biological processes, ranging from gene expression through protein manufacturing. Short double-stranded RNAs participate in selective degradation of messenger RNA transcripts (RNA interference); folded RNAs can catalyze reactions, or switch genes on and off; in conjunction with numerous proteins, RNAs fold into large molecular machines, like the protein-manufacturing ribosome. Furthermore, because small RNAs can be designed to selectivity bind specific targets, these molecules have enormous potential as therapeutics. These widely varying roles are enabled by RNA's structural versatility. We propose to test new hypotheses about the roles of ions and RNA architecture in RNA self-assembly or folding. We will use time resolved small angle x-ray scattering to report the time-dependent formation of global structures, time-resolved hydroxyl radical footprinting to report the formation of individual contacts within the folding molecule, and time-resolved fluorescence methods to report specific intramolecular distances during folding. To enhance experimental studies, we propose to develop efficient atomically detailed simulations of the kinetics and thermodynamics of RNA folding. Initially, these coupled tools will be applied to further quantify the important role of ions in RNA folding. We will also study folding of different classes of RNA enzymes or ribozymes to explore the role of RNA architecture in folding. Our long term goal is to understand the factors involved in RNA folding. Such knowledge is essential for the efficient development and application of RNA-based therapeutics. PUBLIC HEALTH RELEVANCE: RNA molecules can "fold" into biologically active structures that carry out a wide variety of functions. The numerous roles assumed by RNA highlight its usefulness and its great potential as a therapeutic molecule or a target for other therapeutics. These studies will enable us to better understand how RNA structures assemble, thus will teach us how to more efficiently design RNAs for application in medicine or biotechnology.

描述（由申请人提供）：与最早的模型表明其仅作为信使起作用相反，现在已知RNA参与无数基本生物过程，从基因表达到蛋白质制造。短的双链RNA参与信使RNA转录物的选择性降解（RNA干扰）;折叠的RNA可以催化反应，或开关基因;与许多蛋白质结合，RNA折叠成大分子机器，如蛋白质制造核糖体。此外，由于小RNA可以被设计为选择性结合特定靶点，因此这些分子作为治疗药物具有巨大的潜力。这些广泛不同的作用是由RNA的结构多样性实现的。我们建议测试离子和RNA结构在RNA自组装或折叠中的作用的新假设。我们将使用时间分辨的小角度X射线散射来报告全球结构的时间依赖性形成，时间分辨的羟基自由基足迹报告折叠分子内的单个接触的形成，和时间分辨的荧光方法报告折叠过程中的特定分子内距离。为了加强实验研究，我们建议开发有效的原子详细模拟RNA折叠的动力学和热力学。最初，这些耦合工具将被应用于进一步量化离子在RNA折叠中的重要作用。我们还将研究不同种类的RNA酶或核酶的折叠，以探索RNA结构在折叠中的作用。我们的长期目标是了解参与RNA折叠的因素。这些知识对于基于RNA的治疗方法的有效开发和应用至关重要。公共卫生相关性：RNA分子可以“折叠”成生物活性结构，执行各种功能。RNA所承担的众多角色突出了其作为治疗分子或其他治疗靶点的有用性和巨大潜力。这些研究将使我们能够更好地了解RNA结构如何组装，从而教我们如何更有效地设计RNA以应用于医学或生物技术。