Modeling Ribosomal Control, Function and Assembly

核糖体控制、功能和组装建模

• 批准号: 7290378
• 负责人: ROBERT L JERNIGAN
• 金额: $ 25.14万
• 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/7290378
• 关键词: Active Sites; Address; Adopted; Affect; Amino Acyl Transfer RNA; Antibiotics; Antineoplastic Agents; Binding; Binding Sites; Biochemical; Biological Process; Cellular biology; Cereals; Chemicals; Collaborations; Collection; Communities; Complex; Comprehension; Computer Assisted; Computing Methodologies; Data; Databases; Deposition; Depth; Drug Design; Equilibrium; Foundations; Goals; Hereditary Disease; Imagery; Individual; Internet; Laboratories; Learning; Literature; Messenger RNA; Methodology; Methods; Modeling; Modification; Molecular; Molecular Conformation; Molecular Structure; Molecular Target; Motion; Numbers; Object Attachment; Outcome; Pathway interactions; Pattern; Peptides; Peptidyltransferase; Pharmaceutical Preparations; Placement; Positioning Attribute; Printing; Process; Protein Biosynthesis; Protein Dynamics; Protein Subunits; Proteins; RNA; RNA Folding; Reporting; Research; Research Personnel; Resort; Ribosomes; Role; Simulate; Site; Solutions; Staging; Structure; System; Time; Transfer RNA; Validation; Work; base; cellular imaging; computerized tools; concept; driving force; experience; foot; innovation; insight; interest; molecular modeling; network models; novel therapeutics; programs; protein folding; research study; scaffold; simulation; single-molecule FRET; small molecule; success; theories; tool

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标，但其实际作用机理尚未详细了解。现在，不同状态中核糖体的多种结构的可用性为实现总体目标提供了一个重要的机会，以揭示TRNA和mRNA易位的步骤，蛋白质伸长以及30S亚基蛋白质成分的组装到16S RNA上。该项目建立在以前的成功基础上，以1）实验脚打印实验，用于鉴定组装过程中的中间体，以及2）通过粗糙的结构来计算蛋白质和RNA的重要大域运动，以弹性网络表示，通过正常模式分析揭示结构运动。因此，计算整个核糖体结构的运动，从而产生有关各种组件如何共同或对立的信息以及可视化运动的信息。通过采用混合的粗粒方法，大型域运动以及结合位点，活动位点和铰链的复杂原子细节在结构中揭示。对构象变化和功能机制的预测变化的验证将来自实验数据，例如FRET和单分子实验。对于30S核糖体亚基组装，将通过利用这些强大的计算来生成与指示构象变化的新修饰实验相一致的结构，以生成结构，为组装中间体开发分子模型。实验和计算的创新协调将增强两组研究的实用性。预计核糖体的结构动力学以及各种已知的结构，生化和序列保守数据的广泛模拟有望产生有关这种核糖核蛋白机的功能的重要新分子细节，并为新的治疗方法开辟了前景。