MicroED for Joe Molecule

19 October 2018 - Cryoing all the way to ChemRxiv

GonenStoltz2018.PNGWas getting a lot of mentions on Twitter this week: MicroED for small ordinary molecules by Brian Stoltz and Tamir Gonen. (DOI) Organic chemists are excited because of the promise of a new easy-to-exploit tool for molecular structure elucidation.

Transmission electron cryomicroscopy (cryoTEM) has been around for some time. The technique allows the analysis of complex biomolecules in their natural environment (in solution, but frozen) and not necessarily as a crystal. In traditional X-ray diffraction any crystal suitable for analysis has to be large and picture-prefect, getting one is one of the dark arts in chemistry. By the way, for those confused, with either electrons or x-rays the technique can be called crystallography, diffraction or microscopy without an apparent master plan. CryoTEM (microscopy that is) was the main event of the 2017 Nobel Prize in Chemistry.

Earlier in In 2013 Gonen et al. (DOI) demonstrated for the first time that it was possible to use microcrystals for the job and called their invention MicroED (diffraction that is). This team still was about biomolecules (lysozome) but the new work targets small regular molecules. For this Gonen teamed up with Stoltz (a total synthesis chemist) and the results were surprising.

A commercial powder sample of progesterone was cooled and placed in a commercially available cryo electron microscope (a Talos Arctica). It took only 30 minutes data collection (manually targeting a microcrystal as with any microscope and scan) to get 1 angstrom resolution. Some features in this Talos machine (the size of several fridges) certainly helped. The authors emphasize the crystals can be one billionth of the size needed for regular X-ray diffraction. The procedure was successfully demonstrated to wok with column chromatography samples, it was demonstrated to work at the proton level, and demonstrated to work with mixtures.

The work was published in ChemRxiv, the brand-new preprint service/server launched by the ACS. This initiative was about time, it should put the whole insane-paywall / open-access / Scihub discussion to bed if only the chemical scientists remember to pay a regular visit. This blog is also delighted there is a chemRchive API and that metadata mining is allowed!