Computational/Experimental Modeling of Aqueous Environments in Biology

描述(申请人提供)：这项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来开发现实的细胞质环境。虽然已经投入了大量的精力来开发蛋白质、核酸、糖、膜等分子内相互作用的势能函数，但将水模型的新发展集成到生物分子力场中的工作一直滞后。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了水对生物分子的溶剂化性质，但缺乏用于溶质-水相互作用作为靶标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，并开发新的、基于结构的水、离子和共溶质的溶质-水势，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，Na+、K+、Cl-、NO2-和NO3-被选为细胞环境中的重要成分。新的实验将使用同位素替代中子衍射(NDIS)，这是一种分离溶质-溶质、溶质-水和水-水关联的强大方法，以产生高分辨率的溶质-水结构数据。尽管存在一些感兴趣的解的中子衍射数据，但最近在束流强度、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必要的更高精度。此外，使用新的模拟对某些对使用部分结构因子 将探索有助于分离中子数据中不同对的潜力。将模拟的结构因子进行反变换，并在Q空间中直接与实验数据进行比较，从而形成模拟与实验之间的反馈回路。水势将使用软粘性偶极-四极-八极(SSDQO)模型，该模型由以整个分子的单一位置为中心的分子多极组成。SSDQO在广泛的条件下再现了液态水的许多性质，比典型的模型更好地模拟了水分子的量子力学电子密度的静电学，但在计算上是有效的。开发将在广泛使用的生物分子模拟程序CHARMM中进行。本研究的具体目的是：(1)确定高精度的离子-水溶液的实验结构(2)利用新的数据建立离子-SSDQO力场

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