Multi-Scale Dynamic Modeling of RNA Folding and Assembly

描述（由申请人提供）：自组装大分子机器，如核糖体和剪接体，是基本细胞过程的核心，包括转录，mRNA加工，翻译和DNA复制。创建导致其组装和功能构象的步骤序列的定量和预测性描述对于实现对细胞过程的预测性理解是必要的。组成大分子机器的大量组件导致高度复杂的组装反应。研究这些反应的通量和各种实验方法的最新发展提供了丰富的信息。集成这些数据并构建装配过程的一致描述需要开发复杂的算法，这些算法可以集成多尺度数据并利用大型分布式计算网格不断增长的能力。本提案概述了新算法的扩展和应用，该算法基于反应的动力学测量来创建分子组装过程的定量和预测结构和动态描述。这些算法的发展，结合对30S核糖体亚基组装反应的大量数据集的获取，将被用于创建这个关键分子机器的组装反应的非常详细的定量描述。该描述将极大地加深我们对分子组装的理解，因为它将预测可能组装途径的数量和复杂性，并建立机器中RNA和蛋白质组分之间的协作程度。

DESCRIPTION (provided by applicant): Self-assembling macromolecular machines such as the ribosome and spliceosome are central to fundamental cellular processes including transcription, mRNA processing, translation, and DNA replication. Creating a quantitative and predictive description of the sequence of steps leading to their assembled and functional conformation is necessary to achieve a predictive understanding of cellular processes. The large number of components that make up a macromolecular machine result in a highly complex assembly reaction. Recent developments in the throughput and variety of experimental approaches that probe these reactions provide a cornucopia of information. Integrating these data and building consistent descriptions of the assembly process requires the development of sophisticated algorithms that integrate multi-scale data and leverage the ever-increasing power of large distributed computing grids. This proposal outlines the extension and application of novel algorithms that create quantitative and predictive structural and dynamic descriptions of molecular assembly processes based on kinetic measurements of the reaction. These algorithmic developments, in conjunction with the acquisition of large data sets on the assembly reaction of the 30S ribosomal subunit, will be used to create a highly detailed quantitative description of the assembly reaction of this critical molecular machine. The description will greatly deepen our understanding of molecular assembly, as it will predict the number and complexity of the possible assembly pathways, as well as establish the degree of cooperativity between the RNA and protein components of the machine. Public Health Statement: Like all machines capable of carrying out complex tasks, the ribosome is comprised of many different components. By understanding how these components come together to make a fully functional molecule, we are effectively reverse engineering the machine. This new understanding will help us enhance, inhibit and/or modify the function of the machine. One direct application of this work is the development of novel antibiotics, as the bacterial ribosome is a major pharmaceutical target. Furthermore, a detailed blueprint of the assembly process will significantly improve our ability to engineer novel molecular machines with entirely new function.