Observations of the birth of crystals

Picture of GI crystals
A team of researchers from the University of Brussels, the Eindhoven University of Technology and the Institut des Sciences de la Terre (ISTerre/OSUG, CNRS / Université Savoie Mont Blanc / IRD / IFSTTAR / Université Grenoble Alpes) in Grenoble, have uncovered the molecular details of polymorph selection of macromolecule crystals. This result has been published on April 5th in Nature

Crystallizing macromolecules - a required step to understand the structure of proteins, the building blocks of life - can be excruciatingly difficult. This in part is because we still do not fully understand how a crystal is “born”. It is well know that crystals are formed through the spontaneous grouping of molecules, adopting a periodic structure in three-dimensions, but how exactly molecules realize this feat is still a mystery. To add some more complexity to the problem, a single molecule can also organize itself into different crystalline structures, called polymorphs. These polymorphs usually have different physical properties, which can have a profound effect on the final characteristics of the formed material. For example, ice and cacao crystal polymorphs will dictate the quality of our much-loved ice cream and chocolates. In the case of protein crystals, polymorphs are important because they will have, among others, different dissolution rates, which is relevant for drug delivery applications. At present, controlling the crystallization process to obtain the polymorph of choice is challenging because the mechanisms underlying polymorph selection are still unclear.

By using cryo-transmission electron microscopy, this interdisciplinary team managed to image the “birth” of protein crystals with molecular resolution, uncovering a rather complex hierarchical process that involves different self-assembly stages at increasing length scales. These observations are the first-in-their-kind and provide a new way to gain information on the self-assembly processes of macromolecules into larger structures. But, the team went one step further, and mapped the nucleation pathways of multiple polymorphs. They showed that polymorph selection is dictated by the architecture of the smallest possible fragments formed at early time-points of crystallization process. Once such precursor structures are formed, the outcome of the process is decided. By analyzing and understanding the differences in structure of the various nuclei, the authors developed strategies to guide the polymorph selection process. This was achieved by tuning, through site-directed mutagenesis, the different modes of interaction that exist between the macromolecules, and thus “pushing” the outcome of the nucleation process in one direction or another.
© A.E.S. Van Driessche et al.

In a nutshell, these findings greatly advance our fundamental understanding of nucleation and polymorph selection. These insights are not only relevant for macromolecules but can also be translated to other substances that form crystals (such as pharmaceutical compounds or inorganic solids of industrial interest). Moreover, the experimental methodology developed for this study opens a new avenue to follow protein self-assembly processes that are implicated in a range of pathological disorders, such as liquid-liquid phase separation in eye cataract formation or the formation of amyloid fibers associated with a range of neurological disorders.


Alexander E. S. Van Driessche, Nani Van Gerven, Paul H. H. Bomans, Rick R. M. Joosten, Heiner Friedrich, David Gil-Carton, Nico A. J. M. Sommerdijk & Mike Sleutel, Molecular nucleation mechanisms and control strategies for crystal polymorph selection, Nature 556, 89-94, 5 avril 2018, doi:10.1038/nature25971

Local scientific contact

- Alexander Van Driessche, ISTerre/OSUG | alexander.van-driessche univ-grenoble-alpes.fr | 04 76 63 51 94

This article has been published by

- l’institut national des sciences de l’Univers du CNRS (INSU)