Small and macromolecule crystal structures solved with 3D electron diffraction: a new tool in nnaocrystallogaphy

Crystallography of nanocrystals is a challenge for both organic and macromolecular structure determination. The availability of a technique, which could deliver diffraction data of structure solution quality on nanocrystals may represent a breakthrough in both fields. In macromolecular crystallography since the crystallization of large crystals is the hardest step and in organic crystallography since more and more active pharmaceutical ingredients require nanocrystalline formulations. Among different approaches, 3D electron diffraction (ED) allows single diffraction experiments on crystalline domains of few hundreds of nanometers. Additionally, it turned out that this method also significantly reduces the dynamical scattering, and therefore is extremely efficient for the structure determination of numerous nanocrystalline compounds. Starting from 2013, the availability of new detectors have led to the development of extremely low-dose acquisition protocols, which allow the characterization of highly beam sensitive materials, like macromolecules and pharmaceuticals. Here, we report the ab-initio structure determination obtained by 3D ED of a novel, previously unobserved, monoclinic polymorph of hen egg-white lysozyme and of the promising analgesic and anti-arthritic medicament orthocetamol. Orhtocetamol is a regioisomer of the well-known drug paracetamol, whose crystal structure could not be solved by any other diffraction technique, because coherent domains are only 50-100 nm large and are affected by pseudo-symmetry and twinning