The hydrophobic effect characterises the thermodynamic signature of amyloid fibril growth

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  • Juami Hermine Mariama van Gils, Computer Science Department, Center for Integrative Bioinformatics (IBIVU), VU University, Amsterdam, The Netherlands.
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  • Erik van Dijk, Computer Science Department, Center for Integrative Bioinformatics (IBIVU), VU University, Amsterdam, The Netherlands.
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  • Alessia Peduzzo, Institute of Physical Biology, University of Düsseldorf, Düsseldorf, Germany.
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  • Alexander Hofmann, Institute of Biochemical Plant Physiology, University of Düsseldorf, Düsseldorf, Germany.
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  • Nicola Vettore, Institute of Physical Biology, University of Düsseldorf, Düsseldorf, Germany.
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  • Marie P Schützmann, Institute of Physical Biology, University of Düsseldorf, Düsseldorf, Germany.
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  • Georg Groth, Institute of Biochemical Plant Physiology, University of Düsseldorf, Düsseldorf, Germany.
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  • Halima Mouhib, Universitée Paris-Est, Laboratoire Modélisation et Simulation Multi Echelle, MSME UMR 8208 CNRS, 5 bd Descartes, 77454 Marne-la-Vallée, France.
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  • Daniel E Otzen
  • Alexander K Buell, Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark.
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  • Sanne Abeln, Computer Science Department, Center for Integrative Bioinformatics (IBIVU), VU University, Amsterdam, The Netherlands.

Many proteins have the potential to aggregate into amyloid fibrils, protein polymers associated with a wide range of human disorders such as Alzheimer's and Parkinson's disease. The thermodynamic stability of amyloid fibrils, in contrast to that of folded proteins, is not well understood: the balance between entropic and enthalpic terms, including the chain entropy and the hydrophobic effect, are poorly characterised. Using a combination of theory, in vitro experiments, simulations of a coarse-grained protein model and meta-data analysis, we delineate the enthalpic and entropic contributions that dominate amyloid fibril elongation. Our prediction of a characteristic temperature-dependent enthalpic signature is confirmed by the performed calorimetric experiments and a meta-analysis over published data. From these results we are able to define the necessary conditions to observe cold denaturation of amyloid fibrils. Overall, we show that amyloid fibril elongation is associated with a negative heat capacity, the magnitude of which correlates closely with the hydrophobic surface area that is buried upon fibril formation, highlighting the importance of hydrophobicity for fibril stability.

Original languageEnglish
JournalPLOS Computational Biology
Volume16
Issue5
Pages (from-to)e1007767
ISSN1553-7358
DOIs
Publication statusE-pub ahead of print - 4 May 2020
Externally publishedYes

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