Our state-of-the-art nuclear magnetic resonance (NMR) facilities enable researchers to study molecular structures, interactions with binding partners, and dynamics of small organic molecules and biomacromolecules (proteins, nucleic acids, and carbohydrates), providing groundbreaking insights into the biological processes that underpin health and disease.
NMR: accelerating the study of biophysics in health and disease
Nuclear magnetic resonance (NMR) is a physical phenomenon involving the nuclei in atoms that takes advantage of the small changes in their behavior that enable them to sense their chemical environment. Scientists can measure these changes using NMR spectrometers and magnetic resonance imaging (MRI) systems, enabling a better understanding of the chemical environment around atoms, the bonds between them, the distances that separate them, and their motions relative to each other. Atomic nuclei are so sensitive to small changes in their environment that scientists can often identify the molecule to which they belong just by very accurately measuring their frequencies. Information about the bonds formed among atoms can be read from NMR spectra, enabling us to determine the molecular structure of a chemical or biological molecule such as a protein, carbohydrate, or strand of DNA or RNA. This can be done not only for single molecules but also mixtures of chemicals or metabolites. NMR can also sense the environment a molecule is encountering and thereby detect interactions with other molecules such as binding proteins or receptors. By zooming in on the shapes and motions of individual molecules and groups of molecules, NMR enables researchers to probe the root causes of various diseases, like Alzheimer’s disease and cancer, and develop and optimize targeted drug therapies.
NMR in biology and medicine at UCSF
Designing new therapies for cancer, stroke, and beyond
NMR has many applications in biomedical sciences, allowing researchers to observe the miniscule molecular interactions necessary for cellular health. For example, it has been used to characterize the biophysical changes that are associated with disease mutations in large protein complexes (AAA+ ATPase), which likely lead to an imbalance of proteins (protein homeostasis) in the cell. At UCSF, NMR has been used in concert with other biophysical methods to aid in the design of small molecule drugs that may be able to correct these disease-causing molecular motions. Compounds designed to target cancer cells (which have an imbalance in their proteins) are starting points for the development of new cancer therapies. NMR at UCSF has also characterized motions in nucleosomes—proteins that are essential for making genes accessible for reading and for packaging chromosomes in the nucleus. Other groups at UCSF have used NMR to help design and optimize proteins that can function as sensors of specific drug molecules. Another very active research area at UCSF is metabalomics, in which NMR allows scientists to analyze and quantify changes in populations of drug or nutrient metabolites in diseased cells and tissues, and report on the molecular basis and progression of disease, as well as the effectiveness of drugs and treatments. Examples include research on and diagnosis of cancer and stroke—just a few examples of the many areas where NMR, in conjunction with many other types of research, can play an vital part in understanding disease and developing new medical treatments.
The UCSF NMR Laboratory houses five state-of-the-art NMR spectrometers (400, 500, 600, and 800 MHz), each consisting of powerful superconducting magnets and associated electronics which detect the NMR signals. These instruments support research at UCSF, local schools, and biotech and pharmaceutical companies. NMR spectrometers enable chemists to analyze the progress of reactions during the synthesis of chemicals and drugs. The larger instruments enable studies of molecular structure and dynamics, as well as ligand binding (small chemicals, drugs, DNA/RNA, and partner proteins), all of which are important for the function of biomacromolecules (proteins, DNA/RNA, and carbohydrates).
Thomas James, PhD, was a pioneer in the development of NMR and magnetic resonance for the study of biology (RNA) and medicine (in vivo studies) and established the UCSF NMR Laboratory in Genentech Hall at the UCSF Mission Bay campus in 2013. This work continues today and has drawn a broad range of additional expertise to UCSF, with many groups using NMR to answer questions relating to biology and medicine.
The director of the UCSF NMR lab, John Gross, PhD, and Associate Director Mark Kelly, PhD, received a broad NMR training: John Gross in solution and solid-state NMR techniques from Robert Guy Griffin (MIT) and Gerhard Wagner (Harvard); and Mark Kelly in protein NMR from Hartmut Oschkinat (European Molecular Biology Laboratory (EMBL), Heidelberg).
Gross and Kelly both apply NMR to study challenging biological systems in their own labs and through collaborations with other groups, along with providing their expertise to researchers at UCSF via the NMR facility.