1.1 GHz NMR looks deeper into biological processes

The new 1.1 GHz NMR spectrometer at St. Jude Children’s Research Hospital will enable researchers to study biomolecules with unprecedented resolution

Original source: Physics World

St. Jude Children’s Research Hospital has taken delivery of the world’s most powerful nuclear magnetic resonance (NMR) spectrometer – the Ascend 1.1 GHz from Bruker. The system will be used by the hospital’s structural biology department to study proteins, DNA, RNA and other biomolecules, with the goal of understanding disease development at the molecular and atomic level.

“This 1.1 GHz system provides unprecedented capabilities and opportunities for us to answer challenging biological questions,” explains department chair Charalampos Kalodimos. “It will be our most important tool to perform research in the area of dynamic molecular machines that are otherwise not amenable to other technologies.”

The first study to be performed on the Ascend 1.1 GHz, for example, will aim to determine the structure of molecular chaperones involved in cancer and neurodegenerative diseases in complex with non-native proteins.

Before they can start these investigations, however, Kalodimos and his team need to commission and set-up the new NMR system. Steps include cooling with liquid nitrogen and then liquid helium to bring the central coils down to 4.2 K, followed by energizing the magnet. “It is hard to predict, but this step – required to bring the magnet to its full field of 25.9 T – can take anywhere from a few weeks to several months,” says Kalodimos.

Ramping up the field

NMR works by placing the sample under test into the device’s magnetic field, which aligns the spins of atomic nuclei (most commonly 1H, 13C and 15N), and then subjecting the sample to radiofrequency waves. The nuclei resonate at different frequencies according to the magnetic field around the atom, and the resulting emission signals provide information as to the molecule’s electronic and chemical structure.

For biological applications, NMR spectroscopy can be used to study protein structures and how they change and interact with other cellular molecules. It can also help researchers determine how these physical properties relate to biological function and, importantly, how they are altered in diseases such as cancer. And as the field strength of the magnet increases, the spectral resolution increases alongside.

For many years, however, the physical properties of low-temperature superconductors (LTS) limited high-resolution NMR to a magnetic field of 23.5 T, equivalent to a 1H resonance frequency of 1.0 GHz. The discovery of high-temperature superconductors (HTS) provided the potential to create even higher magnetic fields. But until recently, challenges in tape manufacturing and superconducting magnet technology hindered progress.

According to Bruker, the key advance enabling the creation of its 1.1 GHz (or 25.9 T) magnet was the development of LTS–HTS hybrid magnet technologies, which required progress in HTS materials manufacturing, testing and tape jointing, as well as magnet stabilization, homogenization, quench protection and force management. The company says that the 1.1 GHz system is also a milestone towards the first 1.2 GHz NMR magnet, now under development.

Kalodimos explains that while Bruker was exclusively responsible for the magnet development, he and his team were involved in providing feedback to help improve the ultra-high field NMR probes needed to study biological samples.

The extremely high resolution provided by the 1.1 GHz spectrometer will allow determination of atomic-resolution structures of large, dynamic protein complexes, which currently cannot be resolved by any existing structural biology tool, Kalodimos explains. “We also expect to be able to visualize transiently populated conformational states that may be key in protein function and could also be targeted for therapeutic reasons,” he tells Physics World.

The new NMR spectrometer is central to the current expansion of St. Jude’s structural biology department, which is also investing in other high-resolution biophysical tools such as cryogenic electron microscopy, X-ray crystallography and single-molecule imaging.

“In our department, we follow an integrated structural biology approach, meaning that we use as many techniques as possible to fully understand how biological systems function,” Kalodimos explains, noting that other investigations in the pipeline for the Ascend 1.1 GHz include studying drug resistance in protein kinases and drug discovery.

“With the expansion of the structural biology department, we are creating the world’s most comprehensive research centre for defining the structure of the molecular machines that carry out basic functions within cells,” adds James Downing, St. Jude president and CEO. “This information will enhance our ability to understand what drives paediatric cancer and other catastrophic diseases of childhood, and, ultimately, advance cures for these diseases.”