CryoEM to usurp NMR? Small molecules succumb

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  • Published: Nov 15, 2018
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: CryoEM to usurp NMR? Small molecules succumb

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Graduate student Tyler Fulton prepares samples of small molecules in a lab at Caltech. Credit: Caltech

Nuclear magnetic resonance (NMR) spectroscopy has been an invaluable tool for fifty years allowing chemists and others to figure out the structures of a vast range of molecules based on inferring connectivity between the atoms particular in small organic molecules. Now, that relative upstart technique electron cryo-microscopy (cryoEM) has been used to provide routine and unambiguous structural determination of small organic molecules that one might see as augmenting NMR studies and perhaps even going one step beyond.

Christopher Jones, Michael Martynowycz, Johan Hattne, Jose Rodriguez, Hosea Nelson, and Tamir Gonen of the University of California, Los Angeles, and Tyler Fulton and Brian Stoltz of the California Institute of Technology, in Pasadena, USA, explain how NRM spectroscopy has been the mainstay of routine organic chemistry and beyond for decades, whereas X-ray crystallography has been limited in its use to some extent in the small molecule arena because of the intrinsic limitations of both the analytes and the technique itself. The team has now shown that the crystallographic cousin of X-ray diffraction, electron cryo-microscopy (cryoEM) method microcrystal electron diffraction (MicroED), which can use nanocrystal powders and a simple approach, achieves high-quality data at lower than 1 angstrom resolution within half an hour.

Low-brow samples

"We took the lowest-brow samples you can get and obtained the highest-quality structures in barely any time," explains Stoltz. "When I first saw the results, my jaw hit the floor." The team explains that the reason their approach works so well with samples of small organic molecules is that although they are using fine powders those nanocrystalline specks contain all the crystal data and that can be extracted with MicroED. "I don't think people realized how common these microcrystals are in the powdery samples," Stoltz adds. "This is like science fiction. I didn't think this would happen in my lifetime - that you could see structures from powders."

The use of MicroED structure determination might now readily be extended to various scientific endeavours from drug discovery and medical analysis to forensic science where small molecules, those of molecular mass less than 900 Daltons can be critical.

Changing synthetic chemistry

Perhaps paradoxically, the slowest step in making a new molecule is not the chemistry but checking that the structure one aims for is the structure in the reaction flask at the end. MicroED might change all that and represent the biggest change in small molecule organic chemistry since the advent of NMR in the 1960s. "In our labs, we have students and postdocs making totally new and unique molecular entities every day," adds Stoltz. "Now we have the power to rapidly figure out what they are. This is going to change synthetic chemistry."

Related Links

ACS Cent Sci 2018, online: "The CryoEM Method MicroED as a Powerful Tool for Small Molecule Structure Determination"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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