National Resource for Advanced NMR Technology OVERALL - Project Summary/Abstract Nuclear magnetic resonance (NMR) spectroscopy is a unique set of experimental tools for understanding the intricacies of biology from macromolecular complexes to complex mixtures, from atomic resolution structure to dynamics on timescales of picoseconds to kiloseconds, from chemistry to functional mechanisms and kinetic rates. No other technology has such breadth and potential for basic and applied research and for interfacing with other technologies, such as X-ray crystallography, small angle X-ray scattering, Cryo-EM, and many other spectroscopic tools. Structural characterization serves as the starting point, providing a framework for understanding biological activities, functional mechanisms and kinetic models that can be added by NMR. Dynamics can be exceptionally well characterized by NMR and this can lead to detailed understanding about how proteins and other macromolecules function, how complexes are formed, and sometimes how kinetic rates are achieved. The solution NMR spectroscopy of complex mixtures has been shown to be particularly useful in combination with mass spectrometry for metabolomics and other complex mixtures. Here, we focus on the frontiers of NMR technology made possible by recent breakthroughs in materials research and instrumentation, and their implementation for a broad user community interested in pursuing fundamental questions at atomic resolution at the forefront of biomedical research. Three TR&Ds advance the sensitivity of NMR each with novel technology ? the first through use of high temperature superconductors for RF coils leading to unique sensitivity for solution NMR spectroscopy. TR&D2 takes advantage of a 600 MHz DNP instrument recently installed at the Magnet Lab that will provide enhanced sensitivity through the transfer of magnetization from electrons to protons. New and much more robust DNP probes with an expanded temperature range will be developed. TR&D3 takes advantage of the 36T Series Connected Hybrid for NMR spectroscopy ? a jump in field strength of more that 50% equivalent to a jump in field strength from 17T (1990) to 23.5T (2016) that occurred over the past 26 years! This will lead to dramatic enhancements in sensitivity and even more spectacular reductions in signal averaging time. The science will be driven by an excellent team of DBPs and even more C&Ss that span a very broad range of science. A major team effort will be placed on training a new generation of NMR users through an annual pair of workshops and dissemination through publications and presentations at meetings, through a wide variety of scientific organizations and the news media; through a dedicated website for this Resource and through our training activities; as well as posting of our training lectures and video of demonstrations.
National Resource for Advanced NMR Technology OVERALL Project Narrative NMR spectroscopy is a primary tool for metabolomics and the structural biology of proteins and membrane proteins and complexes they form, as well as a powerful means for characterizing macromolecular dynamics and functional mechanisms. Here, we advance the sensitivity and spectral resolution of NMR technology in multiple ways that will lead to new tools for biomedical science which provide novel insights into metabolic flux, macromolecular kinetic rates, structure functional relationships for many drug targets, and mechanisms of intrinsically disordered proteins and the fluids they form. We interface to NIH-funded programs aimed at addressing Alzheimer's disease, bacterial biofilms, tuberculosis, HIV viral replication, bacterial drug resistance, insulin resistant diabetes, and drug development.
