STRUCTURAL AND THERMODYNAMICAL PROPERTIES OF COMPLEXES FORMED BY THE HUMAN COMP

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 在这项初步研究中，我们的目的是估计的结构和药物结合特性的复合物所形成的人补体成分C3 D和抑制结构域的S。金黄色葡萄球菌胞外纤维蛋白原结合蛋白（Efb-C）及其两种突变体。该复合物含有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构象的集合，并随后使用标准Amber 9软件包最小化生成的构象，对结合复合物的构象空间进行采样。虽然循环生成阶段本质上是并行的，但由于系统的大尺寸（对于具有全原子表示的复合蛋白质，大约6000个原子），最小化技术涉及大量的消息传递。2.估计前一阶段获得的选定样品构象的平衡性质。估计的性质包括野生型复合物及其突变体的结合自由能和比相互作用能。这将通过Amber 9软件包对选定的结果结构进行分子动力学模拟，并将依赖于Amber的大规模并行能力的利用。Teragrid启动分配将使我们能够：a.执行效率研究并确定将为Amber生产运行提供“最佳点”的处理器数量。B.找到循环生成阶段运行的最佳提交策略。C.执行第一次生产运行并产生可验证的结果。

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.