Molecular nucleation mechanisms and control strategies for crystal polymorph selection

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

Onderzoeksoutput: Bijdrage aan tijdschriftTijdschriftartikelAcademicpeer review

56 Citaten (Scopus)
155 Downloads (Pure)

Samenvatting

The formation of condensed (compacted) protein phases is associated with a wide range of human disorders, such as eye cataracts, amyotrophic lateral sclerosis, sickle cell anaemia and Alzheimer's disease. However, condensed protein phases have their uses: as crystals, they are harnessed by structural biologists to elucidate protein structures, or are used as delivery vehicles for pharmaceutical applications. The physiochemical properties of crystals can vary substantially between different forms or structures ('polymorphs') of the same macromolecule, and dictate their usability in a scientific or industrial context. To gain control over an emerging polymorph, one needs a molecular-level understanding of the pathways that lead to the various macroscopic states and of the mechanisms that govern pathway selection. However, it is still not clear how the embryonic seeds of a macromolecular phase are formed, or how these nuclei affect polymorph selection. Here we use time-resolved cryo-transmission electron microscopy to image the nucleation of crystals of the protein glucose isomerase, and to uncover at molecular resolution the nucleation pathways that lead to two crystalline states and one gelled state. We show that polymorph selection takes place at the earliest stages of structure formation and is based on specific building blocks for each space group. Moreover, we demonstrate control over the system by selectively forming desired polymorphs through site-directed mutagenesis, specifically tuning intermolecular bonding or gel seeding. Our results differ from the present picture of protein nucleation, in that we do not identify a metastable dense liquid as the precursor to the crystalline state. Rather, we observe nucleation events that are driven by oriented attachments between subcritical clusters that already exhibit a degree of crystallinity. These insights suggest ways of controlling macromolecular phase transitions, aiding the development of protein-based drug-delivery systems and macromolecular crystallography.

Originele taal-2Engels
Pagina's (van-tot)89-94
Aantal pagina's6
TijdschriftNature
Volume556
Nummer van het tijdschrift7699
DOI's
StatusGepubliceerd - 4 apr 2018

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  • Pers/Media

    Protein Crystal Nucleation Revealed in Fine Detail

    Heiner Friedrich

    5/04/18

    1 item van Media-aandacht

    Pers / media: Vakinhoudelijk commentaar

    Uitrusting

    Center for Multiscale Electron Microscopy (CMEM)

    Heiner Friedrich (Manager), Rick Joosten (Gebruiker), Demi de Moor (Gebruiker), Pauline Schmit (Gebruiker), Ingeborg Schreur - Piet (Gebruiker), Anne Spoelstra (Gebruiker) & Nina Romme - van Moll (Inhoud)

    Materials and Interface Chemistry

    Uitrusting/faciliteit: Onderzoekslaboratorium

  • Citeer dit

    Van Driessche, A. E. S., Van Gerven, N., Bomans, P. H. H., Joosten, R. R. M., Friedrich, H., Gil-Carton, D., Sommerdijk, N. A. J. M., & Sleutel, M. (2018). Molecular nucleation mechanisms and control strategies for crystal polymorph selection. Nature, 556(7699), 89-94. https://doi.org/10.1038/nature25971