Software for the accurate de novo 3D structure prediction of RNA

用于准确从头预测 RNA 3D 结构的软件

基本信息

批准号：
8244020
负责人：
John SantaLucia
金额：
$ 50.7万
依托单位：
DNA SOFTWARE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2012-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8244020
关键词：
3&apos Untranslated Regions Address Algorithms Attention Biochemical Catalytic RNA Cereals Chemicals Code Communities Computer Architectures Computer software Computer-Aided Design Coupled Crystallography DNA Data Set Databases Development Drug resistance Engineering Escherichia coli Free Energy Functional RNA Gene Expression Regulation Generations Goals Homology Modeling Human Genome Hydrogen Bonding In Vitro Introns Knowledge Length Libraries Link Manuals Messenger RNA Methodology Methods Metric Modeling Modification Molecular Conformation Molecular Structure Nucleic Acid Amplification Tests Nucleic Acids Nucleotides Performance Phase Physics Process Proteins Pseudomonas aeruginosa Publishing RNA RNA Sequences Research Personnel Resolution Resources Ribosomal RNA Ribosomes Running Sampling Series Side Simulate Small RNA Structural Models Structure Techniques Testing Time Torsion Validation Vertebral column Visual Work Yeast Model System Yeasts aptamer base blind drug discovery electron density experience flexibility genome sequencing high end computer improved interest knowledge base molecular dynamics mutant novel phenylalanine-tRNA programs protein complex protein structure prototype public health relevance research study restraint software development success three dimensional structure three-dimensional modeling tool validation studies

项目摘要

DESCRIPTION (provided by applicant): The discovery of new and interesting RNA sequences from genome sequencing projects, and the urgency to unravel their functions, has led to a dramatic push for novel structural determination techniques. Current experimental methods for three dimensional structure determination of nucleic acids such as x-ray crystallography and NMR cannot keep pace with the day to day discovery of sequences that need representative structures to be solved or modeled. Thus, there is a clear need to develop tools for 3D structure prediction given only the primary sequence and when available, experimental constraint information. Compared to proteins, RNA structure prediction has received limited resources, and only recently has the field gained attention by the scientific community. As such, RNA prediction has largely relied on protein prediction methodologies despite the vast intrinsic differences between proteins and nucleic acids. Although many of these tools have shown significant advances in the prediction quality, they have also demonstrated low reliability and are often limited to prediction of very small RNAs. In addition, the majority are either manual or semi-automated, which requires an experienced user and a variety of intermediate software packages. To address such concerns, DNA Software, Inc. (DNAS) has developed an RNA homology modeling software, NA-CAD (Nucleic Acid Computer Aided Design) that has a unique force field specifically optimized for RNA. This tool has demonstrated success in homology modeling of large RNA-protein complexes such as the small ribosomal subunit of Pseudomonas aeruginosa. We would now like to extend NA-CAD to include a component for de novo structure prediction. The force field in NA-CAD and the free energy based secondary structure prediction algorithm in our flagship software product Visual OMP provide an advantageous starting point for developing a unified tool that can accurately predict de novo the tertiary structure of medium to large RNA targets. This proposal addresses the engineering of novel algorithms for handling difficult structural motifs such as multiloops, pseudoknots, and multiple domains and incorporating experimental constraints to improve prediction quality. Additionally, coarse-grained models for representing RNA residues and accelerated classical molecular dynamics simulations will be implemented to increase conformational sampling in a tractable computational time frame. PUBLIC HEALTH RELEVANCE: We propose to develop an accurate, fast, and unified de novo structure prediction tool optimized for medium to large sized RNAs. This tool will generate valuable structural models that will help elucidate the functions of RNAs that do not have solved crystal or NMR structures. The proposed de novo tool will be incorporated into our homology modeling software, NA-CAD, so that it will be able to generate three-dimensional homology models of pharmaceutically relevant RNA targets and to model potential drug-resistant mutants, which will be beneficial to researchers involved in structure-based drug discovery.

描述（由申请人提供）：从基因组测序项目中发现了新的、有趣的 RNA 序列，以及揭示其功能的紧迫性，极大地推动了新型结构测定技术的发展。当前用于测定核酸三维结构的实验方法（例如 X 射线晶体学和 NMR）无法跟上需要解决或建模代表性结构的序列的日常发现。因此，显然需要开发仅给出主序列和实验约束信息（如果可用）的 3D 结构预测工具。与蛋白质相比，RNA结构预测的资源有限，直到最近该领域才受到科学界的关注。因此，尽管蛋白质和核酸之间存在巨大的内在差异，但 RNA 预测在很大程度上依赖于蛋白质预测方法。尽管其中许多工具在预测质量方面显示出显着进步，但它们也表现出较低的可靠性，并且通常仅限于预测非常小的 RNA。此外，大多数都是手动或半自动的，这需要经验丰富的用户和各种中间软件包。为了解决这些问题，DNA Software, Inc. (DNAS) 开发了一种 RNA 同源建模软件 NA-CAD（核酸计算机辅助设计），该软件具有专门针对 RNA 优化的独特力场。该工具已在大型 RNA-蛋白质复合物（例如铜绿假单胞菌的小核糖体亚基）的同源建模方面取得了成功。我们现在想要扩展 NA-CAD 以包含用于从头结构预测的组件。 NA-CAD 中的力场和我们的旗舰软件产品 Visual OMP 中基于自由能的二级结构预测算法为开发可以准确预测中型至大型 RNA 目标的三级结构的统一工具提供了有利的起点。该提案解决了新算法的工程问题，用于处理困难的结构图案，例如多环、假结和多域，并结合实验约束来提高预测质量。此外，将实施用于表示 RNA 残基的粗粒度模型和加速的经典分子动力学模拟，以在易于处理的计算时间范围内增加构象采样。公共健康相关性：我们建议开发一种准确、快速、统一的从头结构预测工具，针对中型到大型 RNA 进行优化。该工具将生成有价值的结构模型，有助于阐明尚未解析晶体或 NMR 结构的 RNA 的功能。所提出的 de novo 工具将被纳入我们的同源建模软件 NA-CAD 中，以便能够生成药学相关 RNA 靶点的三维同源模型并建模潜在的耐药突变体，这将有利于研究人员参与基于结构的药物发现。