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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!

Optical tweezers for chemists

13 October 2018 - Physics

opticaltweezersPerez2018.PNGPart of the 2018 Nobel Prize in Physics was awarded to Arthur Ashkin for his invention of optical tweezers in 1986. If you want to know what these are look no further than Youtube University for example with Styropyro demonstrating levitating nano-diamonds in a laser (link) or Phils Musical Snippets and Interesting Projects with just a laser and a felt tip pen or Atom and Sporks explaining some of the theory behind it (link). The phenomenon is surreal, in the felt tip pen clip, the effect of holding the tip of the pen in the focal point of the laser beam is obvious: the tip is briefly set on fire resulting in smoke and debris. The debris in the path of the laser is clearly visible as a bright hotspot. What happens next makes all the difference, if the laser is moved sideways the hotspot moves as well, the debris is trapped in the laser beam and since when can light push around matter?

This of course gets physicists very excited with a lot of furiously scribbled mathematical equations but chemists have been quick to adopt optical tweezers for all sorts of practical experimentation. As just one example take some very recently published work from the Spanisch IMDEA Nanoscience Institute. In it (link) Emilio Perez et al. try to determine just how much force it takes to move a macrocycle along a thread in a molecular shuttle (coincidently the stuff of the 2016 chemistry Nobel). To do so they attached one end of the thread via a DNA linker to a stationary pipette bead and the macrocycle also via a DNA link to a polystyrene bead trapped in a optical tweezers. A force is exerted on the macrocycle by moving away the laser beam from the pippete with a rate of 200 nm per second. The force required for the macrocycle to overcome a station is in the order of 8 pN comparable to the force required the cancel a DNA hairpin conformation. With a constant force applied it was also possible to build a picture of all the shuttling events taking place.