Fibrils Emerging from Droplets: Molecular Guiding Principles behind Phase Transitions of a Short Peptide‐Based Condensate Studied by Solid‐State NMR**

Chemistry - A European Journal, vol. 29, pp. e202301159

Abstract

Biochemical reactions occurring in highly crowded cellular environments require different means of control to ensure productivity and specificity. Compartmentalization of reagents by liquid-liquid phase separation is one of these means. However, extremely high local protein concentrations of up to 400 mg/ml can result in pathological aggregation into fibrillar amyloid structures, a phenomenon that has been linked to various neurodegenerative diseases. Despite its relevance, the process of liquid-to-solid transition inside condensates is still not well understood at the molecular level. We thus herein use small peptide derivatives that can undergo both liquid-liquid and subsequent liquid-to-solid phase transition as model systems to study both processes. Using solid-state nuclear magnetic resonance (NMR) and transmission electron microscopy (TEM), we compare the structure of condensed states of leucine, tryptophan and phenylalanine containing derivatives, distinguishing between liquid-like condensates, amorphous aggregates and fibrils, respectively. A structural model for the fibrils formed by the phenylalanine derivative was obtained by an NMR-based structure calculation. The fibrils are stabilised by hydrogen bonds and side-chain π-π interactions, which are likely much less pronounced or absent in the liquid and amorphous state. Such noncovalent interactions are equally important for the liquid-to-solid transition of proteins, particularly those related to neurodegenerative diseases.

Authors 6

1. Wojciech P. Lipiński

   Radboud University Nijmegen

   Affiliation as printed

   Radboud University Institute of Molecules and Materials (IMM) Heyendaalseweg 135 6525 AJ Nijmegen the Netherlands

   Radboud University Institute for Molecules and Materials: Radboud Universiteit Institute for Molecules and Materials, Institute for Molecules and Materials, NETHERLANDS

2. Johannes Zehnder

   ETH Zurich · Laboratory of Physical Chemistry

   Affiliation as printed

   Physical Chemistry ETH Zurich Vladimir-Prelog-Weg 2 8093 Zurich Switzerland

   ETH Zurich D-CHAB: Eidgenossische Technische Hochschule Zurich Departement Chemie und Angewandte Biowissenschaften, Laboratory of Physical Chemistry, SWITZERLAND

3. Manzar Abbas

   Radboud University Nijmegen · Radboud Institute for Molecular Life Sciences

   Affiliation as printed

   Radboud University Institute of Molecules and Materials (IMM) Heyendaalseweg 135 6525 AJ Nijmegen the Netherlands

   Radboud University Nijmegen Radboud Institute for Molecular Life Sciences: Radboud Universiteit Radboud Institute for Molecular Life Sciences, Institute for Molecules and Materials, NETHERLANDS

4. Peter Güntert

   ETH Zurich · Tokyo Metropolitan University · Goethe University Frankfurt · Laboratory of Physical Chemistry

   Affiliation as printed

   Department of Chemistry Tokyo Metropolitan University 1-1 Minamiosawa, Hachioji-shi 192-0397 Tokyo Japan

   Institute of Biophysical Chemistry Center for Biomolecular Magnetic Resonance Goethe University Frankfurt am Main Max-von-Laue-Str. 9 60438 Frankfurt am Main Germany

   Physical Chemistry ETH Zurich Vladimir-Prelog-Weg 2 8093 Zurich Switzerland

   ETH Zurich D-CHAB: Eidgenossische Technische Hochschule Zurich Departement Chemie und Angewandte Biowissenschaften, Laboratory of Physical Chemistry, SWITZERLAND

5. Evan Spruijt

   Radboud University Nijmegen

   Affiliation as printed

   Radboud University Institute of Molecules and Materials (IMM) Heyendaalseweg 135 6525 AJ Nijmegen the Netherlands

   Radboud Universiteit Nijmegen Institute for Molecules and Materials: Radboud Universiteit Institute for Molecules and Materials, Institute for Molecules and Materials, NETHERLANDS

6. Thomas Wiegand corresponding Aachen Institute of Technical and Macromolecular Chemistry

   RWTH Aachen University · Max Planck Institute for Chemical Energy Conversion

   Affiliation as printed

   Institute of Technical and Macromolecular Chemistry RWTH Aachen University Worringerweg 2 52074 Aachen Germany

   Max Planck Institute for Chemical Energy Conversion Stiftstr. 34–36, 45470 Mülheim an der Ruhr Germany

   Max-Planck-Institute for Chemical Energy Conversion: Max-Planck-Institut fur chemische Energiekonversion, Magnetresonanz komplexer Materialien, Worringerweg 2, 52074 Aachen, GERMANY