Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid / chemistry*
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Amyloid / metabolism
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Amyloid / physiology*
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Amyloid beta-Peptides / chemistry
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Amyloid beta-Peptides / physiology
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Amyloidogenic Proteins / chemistry
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Amyloidogenic Proteins / physiology
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Humans
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Hydrophobic and Hydrophilic Interactions
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Models, Theoretical
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Molecular Dynamics Simulation
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Protein Denaturation
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Protein Folding
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Temperature
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Thermodynamics
Substances
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Amyloid
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Amyloid beta-Peptides
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Amyloidogenic Proteins
Grants and funding
SA and JvG thank the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NOW,
https://www.nwo.nl/over-nwo/organisatie/nwo-onderdelen/enw) for funding received under project number number 680-91-112. The simulations described in this work were carried out on the Dutch national e-infrastructure with the support of SURF Cooperative (EvD and SA, SH-309-14,
https://userinfo.surfsara.nl/systems/cartesius). AKB thanks the European Molecular Biology Organization (EMBO, grant number ASTF 242.00-2011,
https://www.embo.org/funding-awards/fellowships/short-term-fellowships), Magdalene College, Cambridge for funding (no grant number,
https://www.magd.cam.ac.uk/), and the Parkinson’s and Movement Disorder Foundation (PMDF, no grant number,
https://www.pmdf.org/) for funding and the Novo Nordisk Foundation for support through a Novo Nordisk Foundation Professorship (NNFSA170028392). HM thanks the Centre national de la recherche scientifique (CNRS) InFinity program (no grant number,
http://www.cnrs.fr/) for funding and RWTH Aachen University for a Theodore von Kármán Fellowship (no grant number,
https://www.rwth-aachen.de/cms/root/Forschung/Angebote-fuer-Forschende/ERS-Angebote/ERS-International/~rohj/Theodore-von-Karman-Fellowship-Outgoin/). DEO acknowledges support from the Lundbeck Foundation (grant R276-2018-671,
https://www.lundbeckfonden.com/en/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.