Multi-Scale Dynamic Modeling of RNA Folding and Assembly

自组装的大分子机器，如核糖体和剪接体， 基本的细胞过程，包括转录、mRNA加工、翻译和DNA复制。 创建一个定量的和预测性的描述的顺序的步骤，导致他们的组装和 功能构象对于实现细胞过程的预测性理解是必要的。大 组成一台高分子机器的许多组件导致了高度复杂的装配 反应最近的发展，在吞吐量和各种实验方法，探测这些 反应提供了丰富的信息。整合这些数据并建立一致的描述 装配过程需要开发复杂的算法，以整合多尺度数据 并利用大型分布式计算网格不断增长的能力。该提案概述了 扩展和应用新的算法，创建定量和预测的结构和动态 基于反应动力学测量的分子组装过程的描述。这些 算法的发展，结合对组装反应的大数据集的采集， 30 S核糖体亚基，将被用来创建一个非常详细的定量描述的组装 这个关键分子机器的反应。这一描述将大大加深我们对 分子组装，因为它将预测可能的组装途径的数量和复杂性，以及 以确定机器的RNA和蛋白质成分之间的协同性程度。 公共卫生声明： 像所有能够执行复杂任务的机器一样，核糖体由许多不同的蛋白质组成。 件.通过了解这些成分如何结合在一起形成一个功能齐全的分子， 我们实际上是在对机器进行逆向工程。这种新的理解将帮助我们增强，抑制 和/或修改机器的功能。这项工作的一个直接应用是小说的发展 抗生素，因为细菌核糖体是主要的药物靶标。此外，还提供了 组装过程将大大提高我们设计新型分子机器的能力， 新功能

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 achieving 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.