Crystallography of nanocrystalline materials has witnessed a true revolution in the past 10 years, thanks to the introduction of protocols for 3D acquisition and analysis of electron diffraction data. This method provides single-crystal data of structure solution and refinement quality, allowing the atomic structure determination of those materials that remained hitherto unknown because of their limited crystallinity. Several experimental protocols exist, which share the common idea of sampling a sequence of diffraction patterns while the crystal is tilted around a noncrystallographic axis, namely, the goniometer axis of the transmission electron microscope sample stage. This Outlook reviews most important 3D electron diffraction applications for different kinds of samples and problematics, related with both materials and life sciences. Structure refinement including dynamical scattering is also briefly discussed.

3D Electron Diffraction: The Nanocrystallography Revolution.

The localization of hydrogen atoms is an essential part of crystal structure analysis, but it is difficult because of their small scattering power. We report the direct localization of hydrogen atoms in nanocrystalline materials, achieved using the recently developed approach of dynamical refinement of precession electron diffraction tomography data. We used this method to locate hydrogen atoms in both an organic (paracetamol) and an inorganic (framework cobalt aluminophosphate) material. The results demonstrate that the technique can reliably reveal fine structural details, including the positions of hydrogen atoms in single crystals with micro- to nanosized dimensions.

http://science.sciencemag.org/content/sci/355/6321/166.full.pdf

Hydrogen positions in single nanocrystals revealed by electron diffraction

In 2013 we established a cryo-electron microscopy (cryo-EM) technique called microcrystal electron diffraction (MicroED). Since that time, data collection and analysis schemes have been fine-tuned, and structures for more than 40 different proteins, oligopeptides and organic molecules have been determined. Here we review the MicroED technique and place it in context with other structure-determination methods. We showcase example structures solved by MicroED and provide practical advice to prospective users.

/pdf/the-cryo-em-method-microcrystal-electron-diffraction-microed-46otsd4pxq.pdf

The cryo-EM method microcrystal electron diffraction (MicroED)

Determination of the absolute configuration of organic molecules is essential in drug development and the subsequent approval process. We show that this determination is possible through electron diffraction using nanocrystalline material. Ab initio structure determination by electron diffraction has so far been limited to compounds that maintain their crystallinity after a dose of one electron per square angstrom or more. We present a complete structure analysis of a pharmaceutical cocrystal of sofosbuvir and l-proline, which is about one order of magnitude less stable. Data collection on multiple positions of a crystal and an advanced-intensity extraction procedure enabled us to solve the structure ab initio. We further show that dynamical diffraction effects are strong enough to permit unambiguous determination of the absolute structure of material composed of light scatterers.

https://science.sciencemag.org/content/sci/364/6441/667.full.pdf

Electron diffraction determines molecular absolute configuration in a pharmaceutical nanocrystal.

Single-crystal electron diffraction (SCED) is emerging as an effective technique to determine and refine the structures of unknown nano-sized crystals. In this work, the implementation of the continuous rotation electron diffraction (cRED) method for high-throughput data collection is described. This is achieved through dedicated software that controls the transmission electron microscope and the camera. Crystal tracking can be performed by defocusing every nth diffraction pattern while the crystal rotates, which addresses the problem of the crystal moving out of view of the selected area aperture during rotation. This has greatly increased the number of successful experiments with larger rotation ranges and turned cRED data collection into a high-throughput method. The experimental parameters are logged, and input files for data processing software are written automatically. This reduces the risk of human error, and makes data collection more reproducible and accessible for novice and irregular users. In addition, it is demonstrated how data from the recently developed serial electron diffraction technique can be used to supplement the cRED data collection by automatic screening for suitable crystals using a deep convolutional neural network that can identify promising crystals through the corresponding diffraction data. The screening routine and cRED data collection are demonstrated using a sample of the zeolite mordenite, and the quality of the cRED data is assessed on the basis of the refined crystal structure.

/pdf/high-throughput-continuous-rotation-electron-diffraction-2c7az0mvh9.pdf

High-throughput continuous rotation electron diffraction data acquisition via software automation

Until recently, structure determination by transmission electron microscopy of beam-sensitive three-dimensional nanocrystals required electron diffraction tomography data collection at liquid-nitrogen temperature, in order to reduce radiation damage. Here it is shown that the novel Timepix detector combines a high dynamic range with a very high signal-to-noise ratio and single-electron sensitivity, enabling ab initio phasing of beam-sensitive organic compounds. Low-dose electron diffraction data (∼0.013 e− A−2 s−1) were collected at room temperature with the rotation method. It was ascertained that the data were of sufficient quality for structure solution using direct methods using software developed for X-ray crystallography (XDS, SHELX) and for electron crystallography (ADT3D/PETS, SIR2014).

/pdf/ab-initio-structure-determination-of-nanocrystals-of-organic-1gkeshnt31.pdf

Ab initio structure determination of nanocrystals of organic pharmaceutical compounds by electron diffraction at room temperature using a Timepix quantum area direct electron detector

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Ab initio structure determination of nanocrystals of organic pharmaceutical compounds by electron diffraction at room temperature using a Timepix quantum area direct electron detector