DEVELOPMENT OF A NEXT-GENERATION NUCLEIC ACID FORCE FIELD

下一代核酸力场的开发

• 批准号: 8636493
• 负责人: JAY PONDER
• 金额: $ 28.12万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636493
• 关键词: Accounting; Aminoglycoside Antibiotics; Antibiotics; Attention; Base Pairing; Beet Western Yellows Virus; Binding; Binding Sites; Biochemistry; Biological; Biological Process; Biopolymers; Charge; Computational algorithm; Computer Assisted; Computer Simulation; Computer software; Computing Methodologies; DNA; DNA Sequence Analysis; Data; Development; Drug Design; Electrostatics; Engineering; Future; Gases; Genetic; Heart; Human; Investigation; Ions; Kanamycin; Lead; Libraries; Ligands; Mechanics; Medical; Metals; Methods; Modeling; Molecular Biology; Molecular Conformation; Molecular Models; Neomycin; Nucleic Acids; Outcome; Penetration; Pharmaceutical Preparations; Phase; Physiology; Potential Energy; Property; Proteins; RNA; RNA Binding; Research; Ribosomes; Scientist; Series; Small RNA; Specificity; Structural Biochemistry; Structure; System; Theoretical Studies; Therapeutic Agents; Thermodynamics; Torsion; Vertebral column; Water; Z-Form DNA; Zinc Fingers; base; computer studies; design; electron density; electronic structure; improved; inorganic phosphate; insight; macromolecule; models and simulation; molecular mechanics; molecular modeling; neglect; next generation; novel; novel therapeutics; nucleic acid structure; physical model; public health relevance; quantum; research study; simulation; small molecule; structural biology; sugar; transcription factor; viral RNA

DESCRIPTION (provided by applicant): Biomolecular modeling and simulation lies at the heart of physically inspired methods for understanding molecular biology and structural biochemistry. Empirical force fields have been approaching a generational transition over the past several years, moving away from well- established, well-tuned but intrinsically limited fixed point charge models towards more intricate and accurate polarizable potentials. This research proposes to extend the polarizable AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications) force field to nucleic acid systems. Together with the current AMOEBA protein parameterization, this will provide a consistently derived model for the two major biopolymer classes. The required electrostatic parameter for nucleic acids will be derived from high-level quantum mechanical electronic structure calculations. In order to use AMOEBA for DNA and RNA systems, several new energy functions will be needed to treat currently neglected effects, such as charge transfer, penetration of electron densities, and damping of dispersion at short distance ranges. The resulting next-generation of the AMOEBA force field promises to significantly improve the accuracy of short-range interactions over other currently available force fields. Nucleic acids, and their interaction with ions, small molecules and proteins, underlie much of human biochemistry, physiology and genetics. This research will calibrate the AMOEBA nucleic acid potentials on a series of structural motifs, against drug-RNA binding data, and with respect to interactions with ions. The validated force field will then open future opportunities for modeling of transcription factor interactions with DNA, detailed binding calculations for aminoglycoside antibiotics with the ribosome, and similar problems not approachable at present with polarizable force fields.

描述（由申请人提供）：生物分子建模和模拟是理解分子生物学和结构生物化学的物理启发方法的核心。在过去的几年里，经验力场一直在接近代际转变，从完善的、经过良好调整但本质上有限的定点电荷模型转向更复杂和更准确的极化电势。这项研究提议将可极化的 AMOEBA（生物分子应用原子多极优化能量学）力场扩展到核酸系统。与当前的 AMOEBA 蛋白质参数化一起，这将为两种主要生物聚合物类别提供一致的衍生模型。核酸所需的静电参数将从高级量子力学电子结构计算中得出。为了将 AMOEBA 用于 DNA 和 RNA 系统，需要几种新的能量函数来处理目前被忽视的效应，例如电荷转移、电子密度的穿透以及短距离范围内的色散阻尼。由此产生的下一代 AMOEBA 力场有望比其他当前可用的力场显着提高短程相互作用的准确性。核酸及其与离子、小分子和蛋白质的相互作用是人类生物化学、生理学和遗传学的基础。这项研究将根据药物-RNA 结合数据以及与离子的相互作用，在一系列结构基序上校准 AMOEBA 核酸电位。经过验证的力场将为转录因子与 DNA 相互作用的建模、氨基糖苷类抗生素与核糖体的详细结合计算以及目前极化力场无法解决的类似问题提供机会。