Professors Katie Henzler-Wildman and Chad Rienstra, co-directors of the National Magnetic Resonance Facility at Madison (NMRFAM), have been awarded a P41 grant to pioneer new methods for solid-state NMR. The research is funded by the National Institutes of Health and provides $6.5 million over 5 years.
The project builds on existing NMR technology to extend its reach to the broader scientific community. It includes collaborations between NMRFAM and leading experts in the study of Parkinson's disease, antifungal drug development, blood coagulation, and the function of ion channels and membrane protein transporters.
The P41 focuses on development in three areas: 1) sample preparation that will bridge a gap in current structural biology and enhance understanding of how essential membrane proteins function; 2) instrumentation that improves the sensitivity and resolution of NMR experiments; and 3) algorithms and software to automate tasks that are central to NMR projects.
“Progress in these areas,” said Henzler-Wildman, “will extend NMR application to larger and more complex systems. It will reduce barriers to the use of NMR, and reduce time, cost and effort.”
Prototype nmr probes
NMRFAM has already developed a new 900 MHz probe design, in collaboration with Phoenix NMR (Loveland, CO) that allows researchers to collect spectra of samples for biochemistry projects, and provides improved resolution and sensitivity for the study of inorganic compounds used by chemists, as well as proteins that contain metals. At 900 MHz, the magnet is 420,000 times the strength of the Earth’s magnetic field, the strongest in the facility.
NMRFAM also installed a 750 MHz magnet that is critical to the P41 and expected to contribute to the continuing development of NMR technology at NMRFAM for the next two to three decades.
The magnet, operating at about 350,000 times the strength of the Earth’s magnetic field, offers a unique “wide bore” of 89mm. The “wide bore” refers to the cross section inside the magnet where the probe and sample go in. All other magnets in NMRFAM – and its peer facilities – are “narrow bore” (51mm or less).
“There are no other high-field, wide-bore magnets comparable at any open access NMR facility in North America,” said Rienstra, “so it will provide the user community with the ability to do types of experiments that would otherwise not be possible.”
Delivery of new 750 MHz magnet
The 750 MHz magnet enables researchers to develop new types of NMR technology of directly relevance to the P41, such as probes that can operate at four or five NMR frequencies simultaneously, along with pulse sequences and receivers that provide improved resolution and sensitivity.
The newly installed magnets and customized probes have enabled researchers to solve the first structure of an alpha-synuclein fibril, which causes Parkinson’s disease, and study the antifungal drug, amphotericin, the data from which is helping researchers design better versions of the drug with fewer side effects.
The grant is carried out in collaboration with Assistant Professor Tim Grant, whose work focuses on developing computational tools to utilize NMR structural information alongside cryo-electron microscopy and tomography technologies.
“This unique opportunity at the interface of cryo-EM and NMR,” said Rienstra, “is something that our department and campus are especially well-equipped to pursue. We have now one of the only – perhaps the only – sites in North America where such state-of-the-art capabilities in cryo-EM, cryo-ET, solution NMR and solid-state NMR are all in the same department.”
NMRFAM will release lectures and workshop materials for outreach events to train users in breakthrough methods for solid-state NMR spectroscopy developed with support from the P41.