Computational/Experimental Modeling of Aqueous Environments in Biology

描述（由申请人提供）：本研究的总体目标是改善生物大分子的分子动力学（MD）计算机模拟的势能函数，重点是开发一个现实的细胞质环境，该环境是基于对溶质-溶剂相互作用的基本理解。虽然在开发蛋白质、核酸、糖、膜等的分子内相互作用的势能函数方面已经投入了很多努力，将水模型的新发展纳入生物分子力场的工作已经滞后。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，但缺乏溶质-水相互作用的实验结构数据作为目标，阻碍了我们的努力。因此，在这个合作项目中，我们将确定新的中子衍射实验的结构数据，我们将开发新的，基于结构的水，离子和共溶质，可用于现有的生物分子力场的溶质-水的潜力。 对于这个探索性项目，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-水相关性的强大方法，以生成高分辨率的溶质-水结构数据。虽然存在一些感兴趣的解决方案的中子衍射数据，最近的改进束强度，仪器的稳定性和灵敏度，和数据分析将提供更大的精度所需的参数开发。此外，使用部分结构因子的某些对从模拟使用新的 将探讨有助于分离中子数据中不同对的可能性。模拟的结构因子将被反向转换并直接与Q空间中的实验数据进行比较，从而在模拟和实验之间形成反馈回路。水势将使用软粘性偶极-四极-八极（SSDQO）模型，该模型由整个分子以单个位点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特性，比典型模型更好地模拟了水分子的量子力学电子密度的静电学，并且计算效率很高。开发将在CHARMM，一个广泛使用的生物分子模拟程序。本研究的具体目标是：（1）确定离子-水溶液的高精度实验结构（2）利用新数据建立离子-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