Biophysical & Computational Chemistry Core

计算化学子核心的目的是为项目内的研究人员提供计算/建模支持。计算化学和分子建模技术将用于获得在PPG的不同项目中研究的生物分子复合物中存在的特定分子相互作用的结构/功能洞察力。该子核心将整合项目和项目中其他核心产生的实验数据和理论方法，以产生阐明这些生物系统中相互作用的本质及其结构和功能之间关系所需的结构信息。例如，亚核心将使用分子可视化/构建程序（Pymol、SwissPDBViewer、Autodock4和modeler）、氢-氘交换和小角中子和x射线散射计算，为项目3、2和1中分别研究的生物分子复合物提供原子模型，如蛋白质L13A-RNA复合物、带有HSP-90和caveolin的eNOS复合物和HDL-PON1-MPO复合物。将使用对接（Autodock4）构建复合物不同组分之间的交互界面。对接实验将确定蛋白质-蛋白质复合物的氨基酸残基之间的特定相互作用，或RNA-蛋白质复合物的RNA核苷酸与氨基酸残基之间的相互作用，或脂蛋白的氨基酸残基与脂质之间的相互作用。所有溶剂化系统都将进行分子动力学模拟。将分析模拟得到的轨迹，以确定模拟过程中构象的变化，氢键和盐桥模式的变化，二级结构的变化等。为了研究发生在微秒尺度上的构象变化，并且对生物分子系统的功能很重要，将进行粗粒度的模拟，其中原子分组在一起，并使用头对头的简化力场。从计算/建模调查中得到的理论理解将被项目进一步用于设计新的实验。

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.