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.

项目总结/文摘