Powerful method probes small-molecule structures

Currently, the gold standard for determining small-molecule structures is X-ray crystallography. In this technique, researchers crystallize a small molecule and then bombard the crystal with X-rays, which diffract in complex patterns that reveal the molecule's 3D structure. However, producing large, high-quality crystals is time-consuming or impossible for many compounds. Brian Stoltz, Jose Rodriguez, Hosea Nelson and Tamir Gonen wondered if they could use a form of cryoelectron microscopy to characterize small molecules. Known as microcrystal-electron diffraction (MicroED), this technique was developed 5 years ago to study protein structures. In this technique, electron beams, instead of X-rays, are diffracted from crystals, which can be much smaller than those required for X-ray crystallography.

The researchers first tested MicroED on a sample of powdered progesterone, which contained thousands of nanocrystals. They rotated a single crystal and collected electron diffraction data from different angles, determining the structure of the hormone at high resolution (1 angstrom) in less than 30 minutes, compared with weeks or months for X-ray crystallography. They went on to successfully characterize 11 other natural, synthetic and pharmaceutical products, including acetaminophen, ibuprofen and several antibiotics. The researchers even identified four different molecules in a mixture by studying individual nanocrystals. Using MicroED, the researchers analyzed crystals that were a billionth of the size typically needed for X-ray crystallography. The rapid, precise method has the potential to greatly accelerate research in the fields of synthetic chemistry, natural product chemistry and drug discovery, the researchers say.