The Structure and Modeling Core provides the resources to determine, evaluate, predict and visualize all of the molecular targets of the Program Project, including proteins, RNAs, inhibitors, and their complexes. High resolution x-ray crystallography, computational docking and molecular modeling approaches will be used. Access to detailed structural information is essential for the design of experiments and the evaluation of biological and biochemical data. Core B will generate structural data for all of the Projects within the Program. Crystal structures of HIV-1 protease variants identified in Projects 1 and 7, and their complexes with novel inhibitors developed by combinatorial chemistry in Projects 2 and 6, will be determined using state-of-the-art crystallographic methods. Diffraction quality crystals of target HIV-1 RNA structural elements identified in Project 2 will be obtained by combinatorial methods and their structures determined including those of tight binding aminoglycoside complexes. Diffraction quality crystals of HIV-1 protease bound to RNA aptamers developed in Project 7 will be obtained by combinatorial methods and the crystal structures of these RNA-protein complexes will be determined. The crystallography of HIV protease will build on the extensive experience and contributions of the Wlodawer laboratory. Powerful combinatorial crystallization methods will be applied to target RNAs and RNA:protease complexes, and the full resources of the Stout laboratory will be available for x-ray crystallography. Computational modeling will be applied to all molecular targets. For Project 2 the Core will apply automated docking and computer aided drug design techniques to chemical compounds accessible to synthesis. Database search techniques will identify RNA targets for inhibitor design, and homology modeling will predict RNA structure and inhibitor interactions. For Project 6 automated docking will be used to design half-site inhibitors as lead compounds for click-chemistry, and to analyze their binding and assembly in the HIV-1 protease active site. For Project 7 modeling will be used to evaluate the structures of drug resistant mutants and docking will be used to study the interaction of RNA aptamer models with the Protease surface.
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