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

• 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
• 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' 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

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新的和有趣的RNA序列，以及揭示其功能的紧迫性，导致了对新型结构测定技术的巨大推动。目前用于核酸三维结构测定的实验方法，例如X射线晶体学和核磁共振，无法跟上需要求解或建模代表性结构的序列的日常发现。因此，有一个明确的需要，开发工具的三维结构预测仅给定的主要序列，并在可用时，实验约束信息。与蛋白质相比，RNA结构预测获得的资源有限，直到最近才引起科学界的关注。因此，RNA预测在很大程度上依赖于蛋白质预测方法，尽管蛋白质和核酸之间存在巨大的内在差异。虽然这些工具中的许多已经在预测质量方面显示出显著的进步，但是它们也表现出低可靠性，并且通常限于预测非常小的RNA。此外，大多数是手动或半自动的，这需要有经验的用户和各种中间软件包。为了解决这些问题，DNA软件公司。（DNA）开发了一种RNA同源性建模软件，NA-CAD（核酸计算机辅助设计），其具有专门针对RNA优化的独特力场。该工具已证明在大RNA-蛋白质复合物的同源性建模中是成功的，例如铜绿假单胞菌的小核糖体亚基。我们现在想扩展NA-CAD，以包括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一个统一的工具提供了一个有利的起点，该工具可以准确地从头预测中等到大RNA靶标的三级结构。该建议解决了工程的新算法处理困难的结构图案，如多环，伪结，和多个域，并结合实验约束，以提高预测质量。此外，粗粒度模型代表RNA残基和加速经典分子动力学模拟将实施，以增加在一个易于处理的计算时间框架的构象采样。 公共卫生关系：我们建议开发一个准确，快速，统一的从头结构预测工具，优化中到大尺寸的RNA。该工具将生成有价值的结构模型，这将有助于阐明没有解析晶体或NMR结构的RNA的功能。拟议的从头工具将被纳入我们的同源性建模软件，NA-CAD，使它能够生成三维同源性模型的药物相关的RNA目标和模型潜在的耐药突变体，这将有利于研究人员参与基于结构的药物发现。