Towards solution of the RNA folding problem

致力于解决RNA折叠问题

• 批准号: 7806587
• 负责人: Michael D. Brenowitz
• 金额: $ 34.1万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806587
• 关键词: Affect; Behavior; Biological Models; Biological Process; Catalytic Domain; Cations; Cell physiology; Cells; Chemicals; Complex; Coupling; Data; Development; Elements; Environment; Genetic Transcription; Goals; Human Pathology; In Vitro; Individual; Introns; Kinetics; Life; Link; Measures; Mediating; Messenger RNA; Methods; Microscopic; Modeling; Nature; Nucleotides; Pathology; Pathway interactions; Physical environment; Physiological; Polynucleotides; Population; Process; Protein Binding; Proteins; RNA; RNA Folding; Reaction; Regulatory Element; Resolution; Shipping; Ships; Solutions; Structural Models; Structure; Study models; Temperature; Testing; Time; group I ribozyme; in vivo; mRNA Expression; millisecond; protein structure; public health relevance; research study; simulation; three dimensional structure

DESCRIPTION (provided by applicant): RNA molecules often must fold into distinct three-dimensional structures to exert their biological function. These folded structures may be large or small, long-lived or transient, and/or stable or unstable in nature. The kinetics of RNA folding is characterized by multiple pathways, the population of intermediates and often (but not always) on- and/or off-pathway kinetically trapped species. Our approach to understanding how the RNA is folded is to determine which folding pathways are possible in vitro with the goal of determining the subset that occur in vivo. We computationally integrate local and global measures of folding into "structural-kinetic" models that characterize folding reactions from their earliest steps. Our development of high-throughput methods for the acquisition of time progress curves with millisecond time and single nucleotide spatial resolution allows general hypotheses to be tested against experimental data that is both deep and broad. The proposed studies of group I introns seek to establish quantitative relationships between RNA structure, stability and folding kinetics by critically comparing the folding of phylogenetically related RNA molecules and gentle systematic perturbation of tertiary contacts. The folding of a riboswitch whose structure is homologous to the catalytic core of group I intron is analyzed to determine if these different regulatory elements possess a common folding mechanism. We explore the effect on the observed emergent folding behavior solution variables such as temperature and ionic conditions that affect the microscopic environment of RNA in order to understand the relationships between the physical environment and folding environment. Lastly, we seek to understand how transcription affects RNA folding. PUBLIC HEALTH RELEVANCE: RNA is critical to the function of many cellular processes. Its correct folding is vital for the biological function of these important elements of the cell. However, the link between incorrect RNA folding and physiological malfunctions and pathologies is only started to emerge. We believe that the principles revealed by quantitative study of model systems such as the group I ribozymes will be directly applicable to RNA structures and protein-RNA assemblies linked to human pathologies.

描述（由申请人提供）：RNA分子通常必须折叠成独特的三维结构才能发挥其生物学功能。这些折叠的结构可能是大的或小的，长期的或短暂的，和/或稳定的或不稳定的性质。RNA折叠动力学的特征是多种途径，中间产物和经常（但不总是）在和/或非途径上被动力学捕获的物种的种群。我们了解RNA如何折叠的方法是确定哪些折叠途径在体外是可能的，目的是确定在体内发生的子集。我们通过计算将局部和全局的折叠测量整合到“结构动力学”模型中，该模型从最初的步骤开始表征折叠反应。我们开发的高通量方法用于获取毫秒时间和单核苷酸空间分辨率的时间进度曲线，可以根据深入和广泛的实验数据对一般假设进行测试。拟议的I族内含子研究试图通过严格比较系统发育相关RNA分子的折叠和三级接触的温和系统扰动，建立RNA结构、稳定性和折叠动力学之间的定量关系。分析了结构与I族内含子催化核同源的核糖开关的折叠，以确定这些不同的调节元件是否具有共同的折叠机制。我们探讨了影响RNA微观环境的温度和离子条件等溶液变量对观察到的紧急折叠行为的影响，以了解物理环境与折叠环境之间的关系。最后，我们试图了解转录如何影响RNA折叠。公共卫生相关性：RNA对许多细胞过程的功能至关重要。它的正确折叠对细胞中这些重要元素的生物学功能至关重要。然而，不正确的RNA折叠与生理功能障碍和病理之间的联系才刚刚开始出现。我们相信，通过模型系统（如I组核酶）的定量研究揭示的原理将直接适用于与人类病理相关的RNA结构和蛋白质-RNA组装。