Computational/Experimental Modeling of Aqueous Environments in Biology

生物学中水环境的计算/实验建模

• 批准号: 8427690
• 负责人: JOHN W BRADY
• 金额: $ 24.62万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8427690
• 关键词: Anions; Back; Biological; Biology; Cell physiology; Charge; Computer Simulation; Computers; Cytoplasm; Data; Data Analyses; Development; Disease; Electrostatics; Ensure; Environment; Experimental Models; Feedback; Goals; Health; Individual; Ions; Liquid substance; Mechanics; Membrane; Methods; Modeling; Molecular; NBL1 gene; Neutron Diffraction; Neutrons; Nucleic Acids; Pharmaceutical Preparations; Potential Energy; Property; Proteins; Radial; Research; Resolution; Simulate; Site; Solutions; Solvents; Structure; Temperature; Thermodynamics; Toxin; Virus; Water; aqueous; base; combat; density; design; electron density; improved; instrument; interest; macromolecule; model development; molecular dynamics; pressure; programs; quantum; research study; simulation; solute; sugar; water solution

DESCRIPTION (provided by applicant): The overall goal of this research is to improve potential energy functions for molecular dynamics (MD) computer simulations of biological macromolecules, focusing on developing a realistic cytoplasmic environment that is based on a fundamental understanding of solute-solvent interactions. While much effort has been invested in developing the potential energy functions for intramolecular interactions of proteins, nucleic acids, sugars, membranes, etc., integration of new developments in water models into the biomolecular force fields has lagged. In addition, while most water model development has focused on pure water properties, our model development has also included the solvation properties of water for biological molecules, but the lack of experimental structural data for solute-water interactions to use as targets has hampered our efforts. Thus, in this collaborative project, we will determine structural data from new neutron diffraction experiments and we will develop new, structure-based solute-water potentials for water, ions, and co-solutes that can be used with existing biomolecular force fields. For this exploratory project, Na+, K+, Cl-, NO2-, and NO3- were chosen as important components in the cellular environment. The new experiments will use neutron diffraction with isotopic substitution (NDIS), a powerful method for separating the solute-solute, solute-water and water-water correlations, to generate high- resolution solute-water structural data. Although some neutron diffraction data for the solutions of interest exists, recent improvements in beam intensities, instrument stability and sensitivity, and data analysis will give the greater accuracy necessary for parameter development. In addition, the use of partial structure factors for certain pairs from the simulations using the new potentials to aid the separation of the different pairs in the neutron data will be explored. Simulated structure factors will be back-transformed and directly compared to the experimental data in Q space, thus forming a feedback loop between the simulation and experiment. The water potential will use the soft-sticky dipole-quadrupole-octupole (SSDQO) model, which consists of molecular multipoles centered on a single site for the entire molecule. SSDQO reproduces numerous properties of liquid water over a wide range of conditions, mimics the electrostatics of the quantum mechanical electron density of a water molecule better than typical models, and yet is computationally efficient. Development will be in CHARMM, a widely used biomolecular simulation program. The specific aims of this research are: (1) Determine highly accurate experimental structures of ion-water solutions (2) Develop the ion-SSDQO force field using the new data

描述（由申请人提供）：本研究的总体目标是改进生物大分子的分子动力学（MD）计算机模拟的势能函数，重点是基于对溶质-溶剂相互作用的基本理解，开发一个现实的细胞质环境。虽然在开发蛋白质、核酸、糖、膜等分子内相互作用的势能函数方面投入了大量的努力，但将水模型的新发展整合到生物分子力场方面却滞后。此外，虽然大多数水模型的开发都集中在纯水的性质上，但我们的模型开发也包括水对生物分子的溶剂化性质，但缺乏作为目标的溶质-水相互作用的实验结构数据阻碍了我们的努力。因此，在这个合作项目中，我们将从新的中子衍射实验中确定结构数据，我们将开发新的、基于结构的水、离子和共溶质的溶质-水电位，这些电位可以与现有的生物分子力场一起使用。在这个探索性项目中，选择Na+， K+, Cl-， NO2-和NO3-作为细胞环境中的重要成分。新的实验将使用中子衍射与同位素取代（NDIS），这是一种分离溶质-溶质，溶质-水和水-水相关性的强大方法，以产生高分辨率的溶质-水结构数据。虽然存在一些中子衍射数据，但最近在光束强度，仪器稳定性和灵敏度以及数据分析方面的改进将为参数开发提供更大的准确性。此外，利用局部结构因子对某些对进行了新的模拟