New crystallographic method will help pharmacists and faster computers

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Swapping your left shoe for the right one while putting them on is unpleasant, but swapping molecules in the same way when making medicines can be fatal - instead of a drug poison is produced. A new method invented by a team of international scientists led by Lukas Palatinus from the Institute of Physics of the Czech Academy of Sciences will help prevent this. The unique procedure for determining the position of atoms in crystals was published last week in the Nature Chemistry.

Distinguishing the left leg from the right one is easy, but how do you distinguish between two forms of molecules that are also mirror images of each other, yet not visible even with the best microscope? A team of crystallographers at the Institute of Physics of the Czech Academy of Sciences has been tackling this question for a long time. The current result builds on decades of previous research. It has been performed mostly by Lukáš Palatinus' former postdoc Paul Klar, now at the university of Bremen, and has been contributed to also by colleagues from Stockholm University and University of Hannover.

"If you sweeten your dessert with L-aspartame, it will be sweet, but if you use the mirror-reversed molecule D-aspartame, it will not result in sweet taste. Determining this so-called absolute configuration of molecules is a key part of crystal structure analysis. The newly developed method provides a means to determine it quickly and reliably, even from materials where this has not been possible before or required much more sophisticated techniques," Lukáš Palatinus explains the benefits of the procedure.

1 + 1 = fast, cheap, reliable

To investigate the atomic structure of very small crystals, some of which are much smaller than a micrometer, the researchers used a technique called continuous-rotation 3D electron diffraction. They combined this technique with precise calculations of the effects that describe the behaviour of electrons as they interact with crystals.

The advantage of this combination, and the main contribution of the new publication in Nature Chemistry, is that precise crystal structures, including absolute configurations, are obtained more easily, reliably, quickly, and cheaply than in the case of other techniques. "Determining the position of atoms in crystals of all kinds of materials is of fundamental importance to our daily lives – it affects not only the function of medicines, but also the composition of washing powders or the development of new components for computers," says Lukáš Palatinus.

The developed method has been patented by the team of scientists in Europe, as well as in the United States and China, while the developed software can be used free of charge by academic institutions. The interest in the purchase of the software and licensing the patent has also been expressed by the private sector, especially pharmaceutical companies, which want to use it to help them determine the absolute configuration of, for example, natural products when producing new drugs. It will help prevent similar disasters caused by differences in the effects of mirror-reversed molecules, such as the case of the drug Contergan, which caused developmental defects in the newborns of mothers who took the drug during pregnancy.

P. B. Klar, Y. Krysiak, H. Xu, G. Steciuk, J. Cho, X. Zou, L. Palatinus, Accurate structure models and absolute configuration determination using dynamical effects in continuous-rotation 3D electron diffraction data. Nat. Chem. (2023).