Multi-Scale Dynamic Modeling of RNA Folding and Assembly

RNA 折叠和组装的多尺度动态建模

• 批准号: 7923647
• 负责人: Alain T Laederach
• 金额: $ 14.3万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923647
• 关键词: Algorithms; Antibiotics; Biological Models; Biology; Cell physiology; Complex; Computer software; DNA biosynthesis; Data; Data Set; Deuterium; Development; Engineering; Genetic Programming; Genetic Transcription; Hydroxyl Radical; Informatics; Introns; Kinetics; Lead; Macromolecular Complexes; Measurement; Measures; Messenger RNA; Methodology; Methods; Modeling; Molecular Conformation; Molecular Machines; Molecular Structure; Nature; Nucleotides; Pathway interactions; Performance; Pharmacologic Substance; Positioning Attribute; Process; Protein Binding; Proteins; Public Health; Publishing; RNA; RNA Folding; Reaction; Ribosomal Proteins; Ribosomes; Son of Sevenless Proteins; Spliceosomes; Structural Models; Structure; System; Techniques; Tetrahymena thermophila; Translation Process; Validation; Work; base; cluster computing; combinatorial; direct application; improved; macromolecular assembly; macromolecule; molecular assembly/self assembly; novel

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.

自组装大分子机器，例如核糖体和剪接体是至关重要的 基本的细胞过程，包括转录，mRNA加工，翻译和DNA复制。 对导致组装的步骤的顺序创建定量和预测性描述，并 功能构象对于实现对细胞过程的预测理解是必要的。大 组成大分子机器的组件数量导致一个高度复杂的组件 反应。探测这些的吞吐量和多种实验方法的最新发展 反应提供信息的聚宝盆。整合这些数据并构建一致的描述 组装过程需要开发复杂的算法，以集成多尺度数据 并利用大型分布式计算网格的不断增长的功率。该提议概述了 新型算法的扩展和应用，创建定量和预测性结构和动态 基于反应的动力学测量的分子组装过程的描述。这些 算法开发，结合​​对大型数据集的收购集合反应的采集 30年代的核糖体亚基将用于创建组件的高度详细的定量描述 这款关键分子机的反应。描述将大大加深我们对 分子组件，因为它将预测可能的组装途径的数量和复杂性 当建立机器的RNA和蛋白质成分之间的合作程度。 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 成分。通过了解这些组件如何组合在一起以制造功能齐全的分子， 我们正在有效地对机器进行逆向工程。这种新的理解将有助于我们增强，抑制 和/或修改机器的功能。这项工作的一种直接应用是新颖的发展 抗生素，因为细菌核糖体是主要的药物靶标。此外，详细的蓝图 组装过程将大大提高我们设计新颖分子机器的能​​力 新功能。