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 seconds, from chemistry to functional mechanisms and kinetic processes. 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, mass spectrometry, and many other spectroscopic and analytical tools. Structural characterization serves as the framework for using NMR to understand biological activities, protein-protein and protein interface interactions, functional mechanisms, and kinetic models. Dynamics can be exceptionally well characterized by NMR, which can lead to detailed understanding about how proteins and other macromolecules function, how complexes are formed, and how certain kinetic processes and rates are achieved. The solution NMR spectroscopy of complex mixtures is particularly useful in combination with mass spectrometry for metabolomics and other complex mixtures, whereas solid-state NMR (ssNMR) is uniquely capable of measuring chemical shift and quadrupolar tensors to provide insights into chemical biology. 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 pursuing fundamental questions at atomic resolution at the forefront of biomedical research. Three Technology Development Projects (TDP) advance the sensitivity of NMR, each featuring novel technologies. TDP1 features the use of high temperature superconductors (HTS) for RF coils, leading to high sensitivity for solution NMR spectroscopy. TDP2 takes advantage of our 600 MHz MAS-DNP NMR instrument, which will provide enhanced sensitivity through the transfer of magnetization from electrons to protons. New and much more robust DNP probes with expanded temperature ranges will be developed. TDP3 uses the 36 T Series Connected Hybrid (36T-SCH) and all-HTS 32 T superconducting (32T-SCM) magnets for ssNMR and solution NMR spectroscopy – the 36T-SCH is the highest-field NMR spectrometer in the world, and the 32T-SCM will be the highest-field spectrometer with low-temperature (4-30 K) capabilities for NMR explorations of biosolids. These platforms will lead to dramatic enhancements in sensitivity and spectacular reductions in signal averaging times. The science will be driven by a select team of ten scientists with Driving Biomedical Projects (DBP), and over 30 Collaborative and Service Projects (CSP) and Technology Partnership Projects (TPP) that span a very broad range of biomedical and biochemical research areas. A major team effort will be placed on training a new generation of NMR users through annual workshops, as well as dissemination through publications and presentations at meetings, a wide variety of scientific organizations, news media, a dedicated website for this Resource, training and educational activities, and posting of training lectures and videos of demonstrations.

NMR spectroscopy is a primary tool for metabolomics and the structural biology of proteins, membrane proteins and complexes they form, providing powerful means for understanding how structure, dynamics, and chemistry drive 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 that provide novel insights into metabolic flux, enzyme mechanisms, structure-function relationships for many drug targets, mechanisms of intrinsically disordered proteins, and cell wall structure. We interface to NIH-funded programs aimed at addressing nonalcoholic fatty liver disease, gene regulation, amino acid synthesis, bacterial biofilms, fungal infections, bacterial drug resistance, and drug development.