MINOS will develop new methods and techniques to test the hypothesis that changes in conformation and/or assembly determine biological outcomes. The staff and scientists of the SIBYLS beamline provide comprehensive expertise in the targeted areas of nucleic acid binding proteins. High Throughput (HT) Small Angle X-ray Scattering (SAXS), Macromolecular Crystallography (MX), and hybrid computational methods.MINOS builds upon our results developing and employing SAXS to define accurate conformations andassemblies in solution in combination with PSI high-resolution crystal structures for detail. Biological information involves changes in shape as well as active site chemistry. SAXS provides robust analyses ofshape and conformational change in solution whereas crystallography provides precise information on structural chemistry. Leveraging our existing SAXS and molecular biology expertise, we will innovate new methods and technologies to integrate and advance PSI and community characterizations of key humanproteins and their complexes (with partner proteins, DNA, and RNA). MINOS will work closely with PSI centers and individual researchers to identify promising targets and constructs, optimize solution conditions,and provide solution conformation and assembly results that complement PSI high resolution crystal structures. MINOS will provide new methods, tools, and strategies to characterize key human and higher eukaryotes proteins and their complexes for structural biology and medicine, which have been challengingfor current PSI and community efforts. Technical goals include identifying and optimizing SAXS datacollection strategies for human proteins and their complexes in concert with high resolution structural studies within the PSI centers, rescuing stalled protein targets, and developing hybrid methods andtechniques for easing the bottlenecks that currently place real limits on overall PSI productivity.
The Specific Aims will endeavor to 1) develop and apply innovative HT SAXS methods to solve solutionstructures of PSLBiology defined targets, and 2) use solution scattering technologies to link PSI andcommunity structures to biology. Structures determined by PSI and community collaborations will direct SAXS experiments, test functional implications from SAXS structures,, and provide critical details fordefining conformational trajectories in solution. Collectively the proposesd Aims provide a clear path to leverage PSI 'and research community strengths and technologies for imaging human and higher eukaryote proteins and their complexes with major impacts on biological understanding.

Public Health Relevance

Preventing and treating human disease ultimately relies on an understanding of how proteins, DNA, and RNA control key cellular functions. A major aspect of understanding these key macromolecules is a detailedpicture of their shape, flexibility, and dynamic nature.
MINOS aims to provide new technologies and methods to study dynamic human macromolecules for structural biology and medicine, and will test the hypothesis that changes in the shape and assembly of dynamic macromolecules control biological outcomes in predictable ways, thereby aiding our ability to predict and treat human disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BCMB-R (40))
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Edmonds, Charles G
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Lawrence Berkeley National Laboratory
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