Biophysical & Computational Chemistry Core

计算化学子核心的目的是为项目项目中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被用来获得结构/功能的洞察，在PPG的不同项目内研究的生物分子复合物中存在的特定分子相互作用。该子核心将整合项目和计划中其他核心产生的实验数据与理论方法，以产生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关系所需的结构信息。例如，子核心将为生物分子复合物提供原子模型，如蛋白质L13 A-RNA复合物、eNOS与HSP-90和小窝蛋白的复合物以及HDL-PON 1-MPO复合物，这些复合物分别在项目3、2和1中使用分子可视化/构建程序进行研究（Pymol，SwissPDBViewer，Autodock 4和Modeller），以及氢-氘交换和小角中子和X射线散射计算。将使用对接（Autodock 4）构建复合物不同组分之间的相互作用界面。对接实验将识别蛋白质-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。所有溶剂化系统将进行分子动力学模拟。将分析模拟产生的轨迹以确定模拟期间构象的变化、H-键和盐桥模式的变化、二级结构的变化等。为了研究在微秒尺度上发生的构象变化，并且对生物分子系统的功能性很重要，将进行粗粒度模拟，其中原子被分组在珠中，并使用珠到珠的简化力场。从计算/建模研究中获得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.