Towards solution of the RNA folding problem

项目摘要 RNA分子通常必须折叠成不同的三维结构，以发挥其生物学功能。 功能这些折叠结构可以是大的或小的、长寿命的或短暂的、和/或稳定的或不稳定的。 性质不稳定。RNA折叠的动力学特征在于多个途径， 中间体和经常（但不总是）在和/或在动力学上被捕获的物质。我们 理解RNA如何折叠的方法是确定哪些折叠途径是可能的 目的是确定体内发生的亚群。我们通过计算整合本地 和全球措施的折叠成“结构动力学”模型的特点折叠反应， 最早的步骤。我们开发的高通量方法的采集时间进展 具有毫秒时间和单核苷酸空间分辨率的曲线允许一般假设 与既深又广的实验数据进行了对比。I组内含子的研究建议 试图建立RNA结构、稳定性和折叠动力学之间的定量关系， 批判性地比较了遗传学相关的RNA分子的折叠， 三级接触的扰动。核糖开关的折叠，其结构与 分析I组内含子的催化核心以确定这些不同的调节元件是否具有 一种普通的折叠机构。我们探讨了观察到的紧急折叠行为的影响 影响微观环境的溶液变量，如温度和离子条件 为了理解物理环境和折叠之间的关系， 环境最后，我们试图了解转录如何影响RNA折叠。

Project Summary 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.