This proposal aims to develop technology for dramatically increasing the sensitivity of magnetic resonance imaging. The goal is to develop a """"""""molecular microscope"""""""" to detect, analyze, and image nanoscale entities of relevance to biomedicine. Tools for determining protein structure are central to biological research. Improved tools for determining the three dimensional structure of large macromolecules and aggregate structures are urgently needed. A majority of proteins are not well suited for analysis by current methods because they cannot be isolated in large enough quantities or because they do not form crystals. In this proposal we present plans for developing a cantilever-based molecular microscope that can determine the structure of a single copy of a protein, a task which no current technology can achieve. Such an instrument would revolutionize structural biology, dramatically impacting a broad spectrum of biological processes, disorders, and diseases. ? ? In this proposal we detail a stepwise approach to developing a molecular microscope for imaging single ? biomolecules based on a marriage of atomic force microscope and magnetic resonance imaging technologies.
Our specific aims are: (1) To detect nuclear magnetic resonance in a new way, as a change in the spring constant of a magnetically tipped microcantilever, (2) Fabricate and characterize nanomagnets suitable for single-proton cantilever detected magnetic resonance. Explore experimentally the minimum forces and spring constant changes that can be detected when a thin, ultrasensitive, silicon microcantilever is brought close to a surface, and (3) Develop and test magnetic resonance imaging protocols suited to small ensembles of nuclear spins. ? ?
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