Overview

X-ray crystallography has underpinned the science behind a dozen Nobel Prizes, but the technique still has some major limitations. For a start, it only works with pure single crystals or powdered crystalline solids. This limits it to the extremes of solid morphology. Between these extremes are countless materials whose detailed structure scientists would like to study: from the polycrystalline formulations that emerge from pharmaceutical laboratories to the multifarious deposits of minerals in the earth's crust.

Another constraint of conventional crystallography is that it examines crystals or crystalline powders on the atomic or molecular scale. Materials scientists, nanotechnologists, geologists and others need to work simultaneously on several length scales from the subnanometre to the millimetre.

Total crystallography

TotalCryst will address both of these issues and provide a method for characterising the structure and dynamics of polycrystals on all length scales from the bulk sample down to the atomic level. The NEST Adventure project exploits a three-dimensional approach to measurements which will enable the characterisation of many crystal grains in parallel. Where conventional crystallography probes the three-dimensional atomic layout of a single crystal, the TotalCryst method will determine the atomic arrangement within each grain of a polycrystal, as well as the position and morphology of the grains. It will offer the complete picture, i.e. total crystallography. The technique will provide a level of accuracy usually only obtainable with single crystal studies, and work with very disparate materials from small molecule catalysts and drugs to large proteins.

The ambitious TotalCryst project follows on from the creation of the Three-dimensional X-ray Diffraction (3DXRD) microscope at the European Synchrotron Radiation Facility in France. TotalCryst will radically push the boundaries of this venture, creating a new, faster, higher-resolution instrument called the nanoscope. But it is the mathematics needed to process and analyse the experimental data, as much as the instrumentation, that is the challenge here. The TotalCryst partnership engages an interdisciplinary team of leading data modelling experts from medical imaging, materials science, applied mathematics, computing, and crystallography.

Diverse and dynamic

TotalCryst will test the technique in areas designed to span the breadth of potential applications – pharmaceutical sciences, structural biology and photochemistry. Novo Nordisk (DK) will try using TotalCryst to characterise the crystal structure of drug compounds under development, applying the information to improve methods of synthesis and formulation. The pharmaceutical industry spends more than €1 billion a year structurally characterising drugs for registration. TotalCryst will speed up this process. Moreover, by assessing the content and homogeneity of tablets in a more direct way, the formulation and efficacy of medicines might actually be improved.

For structural biologists, conventional crystallography has always been a double-edged sword. It provides important insights into the structure of proteins, nucleic acids, and other macromolecules. But it is generally difficult to prepare single crystals, particularly in the case of membrane proteins which do not crystallise easily. Furthermore, many biologically important macromolecules suffer from X-ray induced degradation during structure investigation making them difficult to determine or of poor quality. Scientists from Oxford University (UK) will begin using TotalCryst to reduce the problems of radiation damage.

TotalCryst’s technique does not simply grab a snapshot of a material. It will facilitate time-resolved, or dynamic, studies. For the first time, scientists will be able to watch crystal structures changing on all scales, right down to the atomic level. Such prowess makes the approach attractive to materials scientists and chemists, amongst others, studying dynamic processes in their samples, potentially on a femtosecond timescale. At the Max Planck Institute in Germany, TotalCryst researchers will find out how crystal grain size influences the progress of a light-triggered reaction known as photodimerisation.

The polycrystalline materials that TotalCryst can handle are ubiquitous in nature and form the basis of much of modern industry. Furthermore, the technique is well adapted to use at future small table-top synchrotrons, presently under construction. Hence, the project could have considerable impact across medical, life, materials and environmental sciences.

Reference: NEST fact sheet

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