STRUCTURAL AND THERMODYNAMICAL PROPERTIES OF COMPLEXES FORMED BY THE HUMAN COMP

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在这项初步研究中，我们旨在评估人类补体成分C3D与金黄色葡萄球菌胞外纤维蛋白原结合蛋白抑制域(EFB-C)及其两个突变体形成的复合体的结构和热力学结合性质。该复合体含有362个氨基酸。我们的工作将分两个主要阶段进行：1.通过使用内部开发的环建模算法生成低能量构象集合并随后使用标准Amber 9程序包最小化生成的构象，对结合复合体的构象空间进行采样。虽然环生成阶段在本质上是令人尴尬的并行的，但由于系统的大小(对于具有全原子表示的复杂蛋白质，大约6000个原子)，最小化技术涉及大量的消息传递。2.估计在前一阶段获得的选定采样构象的平衡性质。估计的性质包括野生型复合体及其突变体的结合自由能和特定相互作用能。这将通过琥珀9号程序包对选定的结果结构进行分子动力学模拟，并将依赖于琥珀9号大规模并行能力的利用。TeraGrid的启动分配将允许我们：a.执行效率研究，并确定将为琥珀生产运行提供“甜蜜点”的处理器数量。B.找到循环生成阶段运行的最优提交策略。C.执行第一次生产运行并生成可发布的结果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In this initial study we aim to estimate the structural and thermodynamical binding properties of the complex formed by the Human Complement component C3D and the inhibitory domain of S. aureus extracellular fibrinogen-binding protein (Efb-C), and two of its mutants. The complex contains 362 amino acids. Our work will proceed in two main stages: 1. Sampling of the conformational space of the bound complex by generating an ensemble of low-energy conformations using an in-house developed loop modeling algorithm and by subsequently minimizing the generated conformations using the standard Amber 9 package. While the loop generation stage is embarrassingly parallel in nature the minimization technique involves significant amount of message passing due to the systems' large size (approximately 6000 atoms for the complexed protein with all-atom representation). 2. Estimating equilibrium properties of selected sampled conformations obtained in the previous stage. The estimated properties include binding free energy and specific interaction energy for the wildtype complex and its mutants. This will be done using Molecular Dynamics simulations on selected resulting structures through the Amber 9 package and will rely on the utilization of the Amber's massively parallel capabilities. The Teragrid start-up allocation will allow us to: a. Perform the efficiency studies and identify the number of processors which will provide a "sweet spot" for the Amber production runs. b. Find the optimal submit strategy for the loop generation stage runs. c. Perform first production runs and generate publishable results.