Software for Homology Modeling of Ribosomes

核糖体同源建模软件

• 批准号: 7538149
• 负责人: Norm Earl Watkins
• 金额: $ 9.62万
• 依托单位: DNA SOFTWARE, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7538149
• 关键词: 3-Dimensional; Address; Algorithms; Anti-Infective Agents; Antibiotics; Bacterial Proteins; Base Sequence; Bioinformatics; Biological; Biopolymers; Bite; Carbohydrates; Cells; Class; Code; Communities; Complex; Computer Simulation; Computer software; Computers; Count; DNA; Data; Databases; Deposition; Development; Drug Delivery Systems; Drug resistance; Elements; Engineering; Equation; Escherichia coli; Experimental Models; Floods; Foundations; Future; Genbank; Genome; Genomics; Goals; Grant; Growth; Homology Modeling; Hour; Human; Humanities; Hydrogen Bonding; Individual; Investments; Laboratories; Legal patent; Length; Logic; Long-Term Effects; Macromolecular Complexes; Maintenance; Medical; Memory; Methods; Metric; Modeling; Molecular Structure; Nuclear Magnetic Resonance; Nucleotides; Numbers; Object Attachment; Oligonucleotides; Performance; Pharmaceutical Preparations; Phase; Plant Roots; Protein Biosynthesis; Proteins; Pseudomonas aeruginosa; Public Health; RNA; Range; Research; Research Personnel; Ribosomal Proteins; Ribosomal RNA; Ribosomes; Roentgen Rays; Running; Scientist; Score; Screening procedure; Site-Directed Mutagenesis; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Software Engineering; Software Tools; Speed; Standards of Weights and Measures; Staphylococcus aureus; Structure; Techniques; Technology; Testing; Time; Training; Universities; Validation; Water; Weight; Work; X-Ray Crystallography; blind; day; design; desire; drug development; improved; in vivo; insight; interest; laptop; mathematical model; monomer; mutant; pathogen; pathogenic bacteria; protein metabolite; prototype; size; small molecule; software development; three dimensional structure; tool

DESCRIPTION (provided by applicant): The exponential growth of sequence databases in the genomics era was promoted by the desire to understand fundamental macromolecular structural mechanisms, and how these structures interact with oligonucleotides, proteins and metabolites in a cell. However, a huge discrepancy in the number of corresponding 3D structures available exists. Current experimental methods of 3D structure determination, such as X-ray crystallography and Nuclear Magnetic Resonance, can be cumbersome and problematic, requiring a huge time investment as well as a team of experts that are trained in these techniques. To address these concerns software tools were developed to model macromolecular complexes, but they are rudimentary in that they are still very computationally expensive, they cannot model very large macromolecular structures such as the ribosome, they are not unified into a single platform, and they have not been critically evaluated to date. In this Fast Track SBIR application DNA Software, Inc. proposes to extend the functionality of an existing 3D homology structure prediction platform. Our current prototype software, RNA-123, has focused upon RNA and it can already accurately predict the 3D structures of molecules the size of 5S rRNA (~120 nucleotides long) using sequence-based homology modeling. The engineering and extension of the functionality of this software will enable a researcher, for the very first time, to study the structural mechanisms of a whole ribosome. RNA-123 will make it possible to model pathogenic bacterial ribosomes, where no crystal structures currently exist, to exploit them in a timely manner to develop new classes of rationally designed RNA-targeted drugs. This objective will be accomplished in seven specific aims (aims 1-3 in Phase I and aims 1-4 in Phase II): Aim 1.1: Engineer existing 3D prediction technology, RNA-123, and extend its capabilities to allow for the prediction of 3D structures of larger sequences and complexes. Aim 1.2: Predict the 3D structure of 16S rRNA of T. Thermophilus by using the known 3D crystal structure of 16S rRNA of E. coli as a template and vice versa. Aim 1.3: Test the software developed in aim 1.1 by assessing the 16S rRNA structures predicted in aim 1.2. Aim 2.1: To extend the capabilities of the software developed in phase 1 to allow homology modeling of protein-RNA complexes the size of a bacterial or eukaryotic ribosome. Aim 2.2: Predict and evaluate structures for the known complete ribosomes (70S) and ribosomal subunits (30S and 50S) to test the software developed in aims 1 of phase I and II. Aim 2.3: Correlation of predicted 3D structures of E. coli's 16S rRNA mutants with their biological activity. Aim 2.4: Predict 3D structure of the complete ribosomes of P.aeruginosa, and S. aureus, 2 clinically important pathogens. This grant will have long-term effects on the scientific community as a whole, because once the functionality of RNA-123 is extended to be able to homology model an entire ribosome, it can be easily adapted to model biopolymers, DNA, and carbohydrates as well as their complexes with each other, RNA, and drug-like small molecules. RNA-123 will enable scientists with the latest, most accurate bioinformatics tool available, having an immediate impact on all of humanity. PUBLIC HEALTH RELEVANCE: RNA-123 will be a valuable bioinformatics tool, facilitating the work of researchers in both the public and private communities. Scientists will be able to model macromolecular 3-Dimensional structures, having no structural data in the Protein Data Bank, in silico, to better direct their research efforts in the laboratory, thereby saving time and needless expense. The result of this project will be to speed the development of new classes of rationally designed RNA-targeted drugs against pathogenic bacteria having bio-medical and bio-defense implications.

描述（由申请人提供）：基因组学时代序列数据库的指数增长是由了解基本大分子结构机制以及这些结构如何与细胞中的寡核苷酸、蛋白质和代谢物相互作用的愿望推动的。然而，可用的相应 3D 结构的数量存在巨大差异。目前的 3D 结构测定实验方法，例如 X 射线晶体学和核磁共振，可能很麻烦且存在问题，需要投入大量时间以及接受过这些技术培训的专家团队。为了解决这些问题，开发了软件工具来模拟大分子复合物，但它们还很初级，因为它们的计算成本仍然非常高，它们无法模拟非常大的大分子结构（例如核糖体），它们没有统一到单个平台中，并且迄今为止尚未经过严格评估。在此 Fast Track SBIR 应用程序中，DNA Software, Inc. 提议扩展现有 3D 同源结构预测平台的功能。我们当前的原型软件 RNA-123 专注于 RNA，它已经可以使用基于序列的同源模型准确预测 5S rRNA 大小（约 120 个核苷酸长）的分子的 3D 结构。该软件功能的设计和扩展将使研究人员首次能够研究整个核糖体的结构机制。 RNA-123 将能够对目前不存在晶体结构的致病细菌核糖体进行建模，并及时利用它们来开发新型合理设计的 RNA 靶向药物。该目标将通过七个具体目标来实现（第一阶段的目标 1-3 和第二阶段的目标 1-4）： 目标 1.1：设计现有的 3D 预测技术 RNA-123，并扩展其功能以允许预测更大序列和复合物的 3D 结构。目标 1.2：以已知的大肠杆菌 16S rRNA 3D 晶体结构为模板，预测嗜热链球菌 16S rRNA 3D 结构，反之亦然。目标 1.3：通过评估目标 1.2 中预测的 16S rRNA 结构来测试目标 1.1 中开发的软件。目标 2.1：扩展第一阶段开发的软件的功能，以允许对细菌或真核核糖体大小的蛋白质-RNA 复合物进行同源建模。目标 2.2：预测和评估已知完整核糖体 (70S) 和核糖体亚基（30S 和 50S）的结构，以测试第一阶段和第二阶段目标 1 中开发的软件。目标 2.3：大肠杆菌 16S rRNA 突变体的预测 3D 结构与其生物活性的相关性。目标 2.4：预测两种临床重要病原体铜绿假单胞菌和金黄色葡萄球菌的完整核糖体的 3D 结构。这笔资助将对整个科学界产生长期影响，因为一旦 RNA-123 的功能扩展到能够对整个核糖体进行同源建模，它就可以轻松地用于模拟生物聚合物、DNA 和碳水化合物以及它们之间的复合物、RNA 和类药物小分子。 RNA-123 将为科学家提供最新、最准确的生物信息学工具，对全人类产生直接影响。 公共卫生相关性：RNA-123 将成为一种有价值的生物信息学工具，促进公共和私人社区研究人员的工作。科学家将能够在蛋白质数据库中没有结构数据的情况下，通过计算机模拟大分子的 3 维结构，以便更好地指导实验室的研究工作，从而节省时间和不必要的费用。该项目的结果将是加速开发新型合理设计的 RNA 靶向药物，以对抗具有生物医学和生物防御意义的病原菌。