application) The goal of this project is to produce a detailed molecular model of the three amyloid fibrils which are characteristic of AD, B1-40, B1-42 and NAC. The unusual structural properties of amyloid fibrils preclude their analysis by tradition methods of protein structure determination. This project utilizes new solid-state nuclear magnetic resonance (SSNMR) technology to measure interatomic distances. These distances can be used as constraints which limit the possible structures such that a computational procedure can identify likely candidates for further testing. Other techniques, for example, Fourier-transform infrared spectroscopy and x-ray fiber diffraction analysis, will be used experimentally distinguish between various structural models. The model determined in this project will be combined with information about fibril morphology gained from atomic force microscopy studies (Project 3) to produce a working model of fibril structure. In addition to studies of the isolated amyloid fibrils, this project will seek to characterize, at the molecular level, the interaction with amyloid fibrils of compounds which have been found to bind amyloid. Information of this type will be critical for the optimization of amyloid binders. Such compounds will be a critical component of the design of amyloid imaging agents.
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