Software for Structural Bioinformatics of Nucleic Acid

核酸结构生物信息学软件

• 批准号: 7010095
• 负责人: John SantaLucia
• 金额: $ 24.89万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7010095
• 关键词: DNA; RNA; X ray crystallography; bioimaging /biomedical imaging; bioinformatics; computer program /software; computer simulation; computer system design /evaluation; electric field; macromolecule; mathematical model; model design /development; molecular dynamics; nuclear magnetic resonance spectroscopy; nucleic acid structure; structural biology; thermodynamics; three dimensional imaging /topography

DESCRIPTION (provided by applicant): Methods for macromolecular structure determination cannot keep pace with the exponential growth of biological sequence databases. The goal of this proposal is to develop a new software platform for structural bioinformatics of nucleic acids that will allow analysis of existing structures and accurate prediction of 3D structures. This will be achieved in four specific aims: Aim 1: Write software for homology modeling of nucleic acids. Software will be written to "thread" a sequence whose 3D structure is unknown into a known template structure. This methodology will leverage genome sequencing projects by allowing the automated 3D structure prediction of many functional RNAs. Aim 2: Write software for de novo 3D structure prediction of nucleic acids. Secondary structures from a dynamic programming algorithm will be converted into rough 3D structures using a novel BUILDER algorithm that utilizes a motif database. Classical molecular dynamics simulations will be used to refine the structures. The result will be accurate de novo 3D structure predictions of RNA and DNA. Aim 3: Develop an extended forcefield and optimization algorithms for nucleic acids. The AMBER forcefield will be extended to include parameters for the >100 modified nucleotides that occur in natural RNAs. The forcefields will also be extended to include pseudo-potential terms for gap penalties, solution trends in DNA and RNA folding thermodynamics, and experimental restraints. This modified forcefield will be used to rank predicted 3D structures. New geometry optimization algorithms will also be developed. Aim 4: A systematic validation of the quality of predictions of the software produced by Aims 1,2 and 3 will be performed. The software will be used to predict all the published 3D structures determined by X-ray crystallography or NMR. A blind test will be performed by inviting structural biologists to submit unpublished structures for prediction by our algorithms (similar to CASP for proteins).

描述（由申请人提供）： 大分子结构测定方法无法跟上生物序列数据库的指数增长。该提案的目标是开发一个新的核酸结构生物信息学软件平台，允许分析现有结构并准确预测 3D 结构。这将通过四个具体目标来实现： 目标 1：编写核酸同源建模软件。软件将被编写为将 3D 结构未知的序列“串接”到已知的模板结构中。该方法将通过允许自动预测许多功能性 RNA 的 3D 结构来利用基因组测序项目。 目标 2：编写用于核酸从头 3D 结构预测的软件。来自动态编程算法的二级结构将使用利用主题数据库的新颖的 BUILDER 算法转换为粗略的 3D 结构。经典分子动力学模拟将用于完善结构。结果将是对 RNA 和 DNA 进行准确的从头 3D 结构预测。 目标 3：开发核酸的扩展力场和优化算法。 AMBER 力场将扩展到包括天然 RNA 中出现的 >100 个修饰核苷酸的参数。力场还将扩展到包括间隙罚分的赝势项、DNA 和 RNA 折叠热力学的解决方案趋势以及实验限制。这个修改后的力场将用于对预测的 3D 结构进行排序。新的几何优化算法也将被开发。 目标 4：将对目标 1,2 和 3 生成的软件的预测质量进行系统验证。该软件将用于预测所有已发表的由 X 射线晶体学或 NMR 确定的 3D 结构。将通过邀请结构生物学家提交未发表的结构来进行盲测，以便通过我们的算法进行预测（类似于蛋白质的 CASP）。