Biophysical & Computational Chemistry Core

计算化学分核心的目的是为计划项目中的研究人员提供计算/建模支持。计算化学和分子模拟技术将被用来深入了解在PPG不同项目中研究的生物分子复合体中存在的特定分子相互作用的结构/功能。这个分核心将把项目和计划中其他核心产生的实验数据与理论方法结合起来，以产生所需的结构信息，以阐明这些生物系统中相互作用的性质及其结构和功能之间的关系。例如，次核心将提供生物分子复合体的原子模型，如蛋白质L13A-RNA复合体、eNOS与HSP-90和小窝蛋白的复合体，以及高密度脂蛋白-PON1-MPO复合体，这些分别在项目3、2和1中使用分子可视化/构建程序(PYMOL、SwissPDBViewer、Autodock4和Moeller)以及氢-重离子交换和小角中子和X射线散射计算进行研究。复合体不同组件之间的交互界面将使用对接(Autodock4)构建。对接实验将确定蛋白质-蛋白质复合体的氨基酸残基之间、RNA-蛋白质复合体的RNA核苷酸与氨基酸残基之间、或脂蛋白的氨基酸残基与脂类之间的特定相互作用。所有的溶剂化体系都将接受分子动力学模拟。对模拟得到的轨迹进行分析，以确定模拟过程中构象的变化、氢键和盐桥图案的变化、二级结构的变化等。为了研究在微秒尺度上发生的、对生物分子系统的功能很重要的构象变化，将进行粗粒度的模拟，其中原子聚集在珠子中，并使用珠子到珠子的简化力场。从计算/模拟研究中得到的理论理解将进一步被项目用于设计新的实验。

The purpose of Computational Chemistry sub-Core is to provide computational/modeling support for the investigators within the Program Projects. Computational chemistry and molecular modeling techniques will be used to gain structural/functional insight into specific molecular interactions present in the biomolecular complexes studied within different projects of the PPG. This sub-Core will integrate experimental data produced by Projects and other Cores in the Program with theoretical methods in order to produce structural information needed to elucidate the nature of interactions in these biosystems and the relationship between their structure and function. For example, the sub-Core will provide atomistic models for biomolecular complexes like protein L13A-RNA complex, eNOS complex with HSP-90 and caveolin, and HDL-PON1-MPO complex, which are investigated in Projects 3, 2 and 1, respectively, using molecular visualization/building programs (Pymol, SwissPDBViewer, Autodock4 and Modeller), and hydrogen-deuterium exchange and small angle neutron and X-ray scattering calculations. The interaction interface between different components of the complexes will be constructed using docking (Autodock4). The docking experiments will identify specific interactions between amino acid residues for protein-protein complexes, or between RNA nucleotides with amino acid residues for RNA-protein complexes, or between amino acid residues and lipids for lipoproteins. All solvated systems will be subjected to molecular dynamics simulations. The trajectory resulted from the simulation will be analyzed to determine the change in the conformation during simulation, the change in the pattern of H-bonds and salt-bridges, the change in the secondary structure and so forth. To investigate conformational changes that occur on a microsecond scale and are important for the functionality of the biomolecular system, coarse-grained simulations will be performed in which atoms are grouped together in beads and a bead-to-bead simplified force field is used. The theoretical understanding resulted from the computational/modeling investigation will be further used by the Projects to design new experiments.