Modeling Ribosomal Control, Function and Assembly

核糖体控制、功能和组装建模

• 批准号: 7149659
• 负责人: ROBERT L JERNIGAN
• 金额: $ 26.51万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7149659
• 关键词: binding sites; chemical registry /resource; computer simulation; conformation; intermolecular interaction; molecular assembly /self assembly; nucleic acid biosynthesis; protein biosynthesis; protein structure function; ribosomal proteins; ribosomes; translation factor

DESCRIPTION (provided by applicant): The ribosome is a well-known target for antibiotics, genetic diseases, and anti-cancer drugs, but its actual mechanism of action is not yet understood in detail. The availability of a number of structures of the ribosome in different states now presents an important opportunity to achieve the overall goals to unravel the steps involved in the translocation of the tRNAs and mRNA, protein elongation, and the assembly of the 30S subunit protein components onto the 16S RNA scaffold. The project is built upon previous successes in 1) experimental foot printing experiments for identifying intermediates in the assembly process and 2) computing the important large domain motions of proteins and RNAs by coarse-graining the structures, represented as an elastic network, revealing the structural motions through normal mode analysis. Thus it becomes feasible to compute the motions of the entire ribosome structure, yielding information about how the various components engage together or in opposition, as well as visualizing the motions. By adopting a mixed coarse-grained approach, the large domain motions and at the same time the intricate atomic details at binding sites, active sites, and hinges are revealed within the structure. Validation of the predicted changes in conformation and suggested mechanisms of function will come from experimental data such as FRET and single molecule experiments. For the 30S ribosomal subunit assembly, molecular models will be developed for assembly intermediates by utilizing these robust computations to generate structures consistent with new modification experiments indicating conformational changes. This innovative coordination of experiments and computations will enhance the utility of both groups of studies. Extensive simulations of the structural dynamics of the ribosome, combined with the various known structural, biochemical, and sequence conservation data are expected to yield important new molecular details of how this ribonucleo-protein machine functions, opening prospects for new therapeutic approaches.

描述（由申请人提供）：核糖体是抗生素、遗传疾病和抗癌药物的众所周知的靶点，但其实际作用机制尚未详细了解。现在，许多不同状态的核糖体结构的可用性为实现总体目标提供了一个重要的机会，以解开tRNA和mRNA的易位、蛋白质延伸以及30S亚基蛋白质组分组装到16S RNA支架上所涉及的步骤。该项目是建立在以前的成功1）实验足迹实验识别组装过程中的中间体和2）计算蛋白质和RNA的重要大域运动粗粒度的结构，表示为一个弹性网络，揭示结构运动通过正常模式分析。因此，计算整个核糖体结构的运动变得可行，从而产生关于各种组件如何结合在一起或相反的信息，以及可视化运动。通过采用混合粗粒度的方法，大的畴运动，并在同一时间内的结合位点，活性位点和铰链的复杂的原子的细节揭示的结构。预测的构象变化和建议的功能机制的验证将来自实验数据，如FRET和单分子实验。对于30S核糖体亚基组装，将开发组装中间体的分子模型，方法是利用这些稳健的计算生成与指示构象变化的新修饰实验一致的结构。这种创新的实验和计算的协调将提高两组研究的效用。广泛的模拟核糖体的结构动力学，结合各种已知的结构，生物化学和序列保守性数据，预计将产生重要的新的分子细节，这种核糖核蛋白机器的功能，开辟新的治疗方法的前景。