Nuclear magnetic resonance spectroscopy is a technique used to study the structure and composition of various molecules, including proteins associated with Alzheimer’s disease and other diseases. Recently, researchers at the Massachusetts Institute of Technology have developed a method to significantly improve the sensitivity of nuclear magnetic resonance spectroscopy (NMR).
Robert Griffin, a professor of chemistry at Arthur Amos Noyes, said that with this new approach, scientists should be able to analyze structures that took years to decipher within minutes. This new method relies on short pulses of microwave power, allowing researchers to determine the structure of many complex proteins that have been difficult to study to date. “This technology should open up a wide range of fields of chemistry, biology, materials and medical science that are currently inaccessible.” The paper was published in the Sciences Advances.
Traditional nuclear magnetic resonance uses the magnetic properties of the nucleus to reveal the structure of molecules containing these nuclei. By using a strong magnetic field that interacts with nuclear spins of hydrogen and other isotopically labeled atoms (such as carbon or nitrogen), NMR measures the properties of the chemical shifts of these nuclei. These offsets are unique to each atom and can, therefore, be used as fingerprints, which can be further exploited to reveal how these atoms are connected.
The sensitivity of NMR depends on the polarization of the atoms – the measurement of the overall difference in the “up” and “down” nuclear spins in each spin system. The greater the polarization, the higher the sensitivity that can be achieved. Often, researchers attempt to increase the polarization of a sample by applying a stronger magnetic field, up to 35 Tesla.
Another method developed by Griffin and Richard Temkin of the Center for Plasma Science and Fusion at the Massachusetts Institute of Technology over the past 25 years is to further enhance polarization using a technique called Dynamic Nuclear Polarization (DNP). This technique involves transferring the polarization of unpaired electrons from free radicals to the hydrogen, carbon, nitrogen or phosphorous nucleus in the sample under investigation. This increases polarization and makes it easier to discover the structural features of the molecule.
DNP is typically performed by continuously irradiating a sample with high-frequency microwaves using an instrument called a gyrotron. This increases the NMR sensitivity by about 100 times. However, this method requires a lot of power and does not work well at higher magnetic fields, which can provide a higher resolution improvement.
To overcome this problem, the MIT team proposed a way to provide short-pulse microwave radiation instead of continuous microwave radiation. By providing these pulses at a specific frequency, they are able to increase the polarization by a factor of 200. This is similar to the improvement achieved by traditional DNPs, but it requires only 7% of power, unlike conventional DNPs, it can be implemented at higher magnetic fields.
“We can transfer polarization in a very efficient way by effectively using microwave radiation,” Tan said. “For continuous wave illumination, you only need to excite the microwave power, you can’t control the phase or pulse length.”
Researchers say that with the increase in sensitivity, samples that previously required nearly 110 years to analyze can be studied in one day. In scientific advancement papers, they use the standard test molecules (such as glycerol-water mixtures) to prove the technique, but they now plan to use them for more complex molecules.
One of the protein molecules of interest is the amyloid beta protein, which accumulates in the brains of patients with Alzheimer’s disease. The researchers also plan to study various membrane-bound proteins, such as ion channels and rhodopsin, which are light-sensitive proteins in bacterial membranes and human retinas. Because of its high sensitivity, this method can obtain useful data from a smaller sample size, which makes it easier to study proteins that are difficult to obtain in large quantities.
Kong Ooi Tan, Chen Yang, Ralph T. Weber, Guinevere Mathies, and Robert G. Griffin. Time-optimized pulsed dynamic nuclear polarization. Science Advances, 2019 DOI: 10.1126/sciadv.aav6909