This proposal describes the mission and strategic plans for of a Biomedical Technology Development and Dissemination Center (RM1) entitled Center on Macromolecular Dynamics by NMR Spectroscopy (CoMD/NMR). Located at the New York Structural Biology Center, CoMD/NMR has developed new experimental and computational techniques in NMR spectroscopy, including both structure and dynamics methods for both solution and solid state NMR. Here we focus mainly on spin relaxation methods, which have already had great impact for characterizing protein and nucleic acid conformational dynamics during biological processes including ligand recognition, allosterism, oligomerization, catalysis, and folding. The central challenge addressed by CoMD/NMR is to break down the high activation barrier for new users to apply advanced NMR spectroscopic and computational methods and thereby make sophisticated NMR approaches available to a wide biological research community. To do so, CoMD/NMR addresses four primary obstacles. (i) Because dynamics problems for biopolymers are frequently underdetermined, we develop incisive new experiments, pulse sequences and computational methods. (ii) Because access to advanced NMR instruments can be a limitation for many users, we provide access to a range of enabling NMR instrumentation, including NMR spectrometers at multiple static magnetic fields, a range of modern probes, dynamic nuclear polarization, rapid-freeze-quench, high-pressure equipment, and field cycling relaxometry, all in a well maintained, staff supported, and multiuser environment. (iii) Because transfer of technology to biologists (and even to NMR spectroscopists) has been hindered by the complexity of the methods, and since time efficient use of the instruments is crucial, we develop robust efficient pipelines to facilitate experimental planning, data acquisition and analysis by non- specialists. (iv) Because biologists with research programs that would benefit from these methods are unaware of the potential, we engage in community outreach and education. A unique strength of our program is the integration of forefront solid state NMR, solution NMR and computational experts, and this proposal highlights synergy across these approaches. Additionally, being situated within the NYSBC, we have excellent partnerships with X-ray diffraction, Cryo EM, and membrane protein production technologies. Given the demanding nature of the three Technology Development Projects (TDPs) proposed herein, we have identified a number of Technology Partnership Projects (TPPs), engaging world leaders in aspects of NMR who have indicated their eagerness to partner with us. Technology development proceeds most effectively when driven by exciting and challenging applications; accordingly, CoMD/NMR will work closely with outstanding local and national investigators through Collaborative and Service Projects (CSP), Driving Biomedical Projects (DBB) and Community Engagement (CE) activities, including extensive training and dissemination programs. Through its various components, CoMD/NMR will impact a diverse range of biological research with human health relatedness, including degenerative diseases, metabolic disorders, and cancer.

This proposal describes the need for and outline of an RM1 BTDD Center on Macromolecular Dynamics by NMR Spectroscopy (CoMD/NMR) situated at the New York Structural Biology Center. The focus of CoMD/NMR is to facilitate access to and adoption of cutting-edge technologies of NMR spin relaxation and associated methods for characterizing protein and nucleic acid conformational dynamics in biological processes, emphasizing functional aspects of oligomerization or assembly and of ligand recognition. The objectives of this proposal impact a diverse range of biological research with human health relevance, including cell signaling (in cancer and cell death pathways), degenerative diseases, metabolic disorders, and cancer.