International Research Fellowship Program: Solid-State NMR Studies of Amyloid Fibrils

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0402114FlindersThe International Research Fellowship Program enables U.S. scientists and engineers to conduct three to twenty-four months of research abroad. The program's awards provide opportunities for joint research, and the use of unique or complementary facilities, expertise and experimental conditions abroad.This award will support a twenty-two-month research fellowship by Dr. Jeremy C. Flinders to work with Dr. Hartmut Oschkinat at Institute for Molecular Pharmacology in Berlin, Germany.Amyloid fibrils are misfolded protein aggregates associated with a number of serious diseases, including prion and Alzheimer's disease, type II diabetes, and Huntington's disease. The exact mechanism of formation for these fibrils is currently not understood, primarily due to a lack of sufficient atomic-level structural information. The structures formed by such misfolding have traditionally been difficult to study, since they comprise long, thin filaments that are insoluble and do not crystallize. They are, however, suitable for study using recent solid-state nuclear magnetic resonance (NMR) techniques. The focus of this research project is determining the high-resolution structure of a model amyloid system and using this information to investigate fibril formation. Since sample quality directly affects the resulting data, current methods of sample preparation are also being optimized. Existing techniques for collecting NMR data are not sufficient for the goals of this project, therefore novel NMR and sample preparation techniques are being developed and refined to gather the needed data for structure determination. Considerable effort is being made to extract structural information from all types of nuclei in samples, despite inherent issues of strong interactions among them. Short and long-range distance constraints obtained are being inputted into structure calculation programs. Also being intensely studied is the kinetics and thermodynamics of fibril formation. Approaching this problem from two fronts allows for a better understanding of the sometimes ambiguous or complicated data collected. A working model of fibril formation is constantly being tested and altered using information from several biochemical and biophysical techniques.