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.
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