Solid state Nuclear Magnetic Resonance (ssNMR) is a proven, powerful tool for discerning structural features of macromolecular complexes important in a wide array of human disease states. The method has contributed to advances in our understanding of Alzheimer's, Parkinson's, and prion diseases, and the molecular basis of bacterial antibiotic resistance. In the past decade the use of dynamic nuclear polarization (DNP) to enhance the sensitivity of these experiments by 100 fold, and thus increase throughput by 4 orders of magnitude has resulted in a revolution in the range of biological questions that can be addressed with this method. At present DNP-enhanced ssNMR requires a wide bore NMR magnet, a cryogenic ssNMR probe for magic angle spinning (MAS), and a high power gyrotron microwave source. This represents a capital investment in laboratory space and equipment not accessible to most institutions, not to mention the high operating costs for cryogenic MAS probes. In this development program we will realize an implementation of DNP-enhanced MAS NMR instrumentation in which the cost of ownership is so significantly reduced as to be accessible to single investigator laboratories. The system to be demonstrated for commercialization will replace the wide bore NMR magnet with a ubiquitous and less expensive standard bore magnet, and employ a frequency agile diode based mm-wave source less than 1/10 the cost of a gyrotron. It will also reduce helium cryogen operating costs by recovering the helium used via adaptation to a standard NMR laboratory helium recovery system. Innovations in quasi- optical microwave power delivery in combination with smaller MAS rotors will provide the same DNP performance as current gyrotron based systems by more effectively focusing the available power to a similar power density and delivering this to the sample. By increasing the accessibility of DNP-enhanced MAS NMR these innovations are expected to accelerate research into the molecular structural basis of a wide array of human disease states.
A number of the most important challenges in human health ranging from Alzheimer's disease to bacterial antibiotic resistance require structural characterization of complex macromolecular assemblies in order to understand the molecular basis of causation, and thereby strategies for curative treatments. Solid state magnetic resonance is especially effective in obtaining such data, and the recent addition of dynamic nuclear polarization can accelerate this 100 to 1000 fold. This project will develop a new class of instrumentation that by virtue of an order magnitude lower acquisition and operating cost will result in more widespread application, and thereby greatly accelerate the research aimed at solving these important problems in human health and disease.
