Development of a Next-Generation Nucleic Acid Force Field

下一代核酸力场的开发

• 批准号: 10000923
• 负责人: JAY PONDER
• 金额: $ 29.05万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000923
• 关键词: Acceleration; Address; Adoption; Algorithmic Software; Algorithms; Amino Acids; Amoeba genus; Antibiotics; Anticodon; Area; Award; Bacterial Infections; Binding; Biological; Biological Phenomena; Biophysics; Biopolymers; Charge; Chemicals; Collaborations; Complex; Computer Models; Computer software; Coupled; DNA; DNA Modification Process; Development; Diagnostic; Disease; Divalent Cations; Electrostatics; Environment; Future; G-Quartets; Generations; Growth; Investigation; Ions; Lead; Letters; Life; Ligands; Malignant Neoplasms; Medical; Methods; Modeling; Modification; Molecular; Nature; Normal Cell; Nucleic Acids; Nucleosides; Nucleotides; Oligonucleotides; Oligopeptides; Outcome; Penetration; Performance; Periodicity; Pharmaceutical Preparations; Physiological; Play; Potential Energy; Property; Proteins; Publishing; RNA; RNA, Ribosomal, 23S; Research Personnel; Research Project Grants; Role; Sampling; Series; Sodium Chloride; Structural Chemistry; Structure; System; Technology; Therapeutic; Therapeutic Agents; Thermodynamics; Time; Transfer RNA; U2 small nuclear RNA; Walking; Work; atomic interactions; base; behavior prediction; computer studies; computerized tools; cost; design; experimental study; high end computer; improved; in silico; insight; intermolecular interaction; locked nucleic acid; molecular dynamics; molecular modeling; mutant; next generation; novel diagnostics; novel therapeutics; nucleic acid structure; open source; parallel computer; parallelization; simulation; simulation software; small molecule; sugar; tool

PROJECT SUMMARY/ABSTRACT Biomolecular simulation is a critical tool for analysis of biopolymer structure and dynamics, investigation of intermolecular interactions, and design of new ligands and drugs. Simulation, in turn, is absolutely dependent on accurate and efficient models of the underlying structural chemistry and energetics in terms of empirical energy functions (“force fields”). Force field technology is currently in the midst of a generational transition from traditional atom-based point charges towards more intricate and accurate potentials using better electrostatic models. This proposal will continue development of the AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications) force field for nucleic acids (NAs), and extend the coverage of the model to naturally and synthetically modified NA components. Coupled with our 2013 AMOEBA protein parameters, the new NA force field will provide a unified model for the most important biomolecular systems. Current NA force fields lag well behind their protein counterparts in their ability to accurately model even the most typical structures under physiological conditions. The next-generation AMOEBA NA force field promises to significantly improve the fidelity and range of nucleic acids modeling. Nucleic acids are the major information carrying molecules of life. Under this research project, we will investigate several key aspects of nucleic acids, and refine the AMOEBA force field. The structures and functions of NAs are highly dependent upon the salt environment. The interplay between RNA local structural dynamics and global/tertiary folding is an intriguing question being addressed experimentally. The ability to model binding energetics, and design small molecule drugs and synthetically modified oligonucleotides will be an important growth area for future medical advances. These studies will be carried out in close collaborations with experimental colleagues. Development of an accurate and transferable next-generation force field will open up new paths toward understand and prediction of the behavior of natural and designed nucleic acid molecules. Finally, adequate sampling of large structures over longer time scales is crucial for future molecular simulations. The proposed development of high-performance, open source, parallel computer software will enable widespread application of the AMOEBA force field to nucleic acids and related biomolecular systems.

项目概要/摘要 生物分子模拟是分析生物聚合物结构和动力学的重要工具， 研究分子间相互作用以及新配体和药物的设计。模拟，在 反过来，绝对依赖于底层结构的准确有效的模型 化学和能量学方面的经验能量函数（“力场”）。力场 技术目前正处于从传统的基于原子的点的代际转变之中 使用更好的静电模型向更复杂和更准确的电势充电。这 提案将继续开发 AMOEBA（原子多极优化能量学） 生物分子应用）核酸（NA）力场，并扩大了覆盖范围 天然和合成修饰的 NA 成分的模型。再加上我们2013年的AMOEBA 蛋白质参数，新的NA力场将为最重要的蛋白质参数提供统一的模型 生物分子系统。目前的 NA 力场远远落后于其蛋白质对应物 能够在生理条件下准确地模拟最典型的结构。这 下一代 AMOEBA NA 力场有望显着提高保真度和范围 核酸建模。 核酸是生命中携带信息的主要分子。在这个研究项目下， 我们将研究核酸的几个关键方面，并完善阿米巴力场。这 NA的结构和功能高度依赖于盐环境。相互作用 RNA局部结构动力学和全局/三级折叠之间是一个有趣的问题 通过实验解决。模拟结合能量和设计小分子的能力 药物和合成修饰寡核苷酸将是未来的重要增长领域 医学进步。这些研究将与实验密切合作进行 同事。精确且可转移的下一代力场的开发即将开启 开辟理解和预测天然和设计核酸行为的新途径 酸分子。 最后，在较长时间尺度上对大型结构进行充分采样对于未来至关重要 分子模拟。建议开发高性能、开源、并行 计算机软件将使阿米巴力场广泛应用于核酸 酸和相关的生物分子系统。