Development of a Next-Generation Nucleic Acid Force Field

下一代核酸力场的开发

• 批准号: 9789332
• 负责人: JAY PONDER
• 金额: $ 29.01万
• 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/9789332
• 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 Simulation; 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; 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.

项目摘要/摘要 生物分子模拟是分析生物聚合物结构和动力学的关键工具， 研究分子间相互作用以及新的配体和药物的设计。模拟，IN 转弯，绝对取决于基础结构的准确有效模型 从经验能量功能（“力场”）方面的化学和能量。力场 技术目前正处于从传统基于原子的角度的世代过渡中 使用更好的静电模型向更复杂和准确的电势充电。这 提案将继续开发变形虫（原子多极优化的能量学 核酸（NAS）的生物分子应用），并扩展了覆盖范围 自然和合成修改的Na组件的模型。加上我们的2013年变形虫 蛋白质参数，新的NA力场将为最重要的统一模型提供统一的模型 生物分子系统。当前的NA力场滞后在其蛋白 能够在生理条件下精确建模最典型的结构。 下一代Amoeba NA力场有望显着提高忠诚度和范围 核酸建模。 核酸是携带生命分子的主要信息。在这个研究项目下， 我们将研究核酸的几个关键方面，并改进变形虫力场。 NAS的结构和功能高度依赖于盐环境。相互作用 RNA局部结构动力学与全球/三级折叠之间是一个有趣的问题 通过实验解决。模拟结合能量并设计小分子的能力 药物和合成修饰的寡核苷酸将是未来的重要增长领域 医疗进步。这些研究将与实验密切合作进行 同事。开发准确且可转移的下一代力场将开放 迈出新的途径，以理解和预测自然和设计核的行为 酸分子。 最后，在较长时间尺度上对大型结构进行足够的采样对于将来至关重要 分子模拟。拟议的高性能，开源，平行的开发 计算机软件将使变形虫力场的宽度应用于核。 酸和相关的生物分子系统。