Wang, Y, Bunce, SJ, Radford, SE orcid.org/0000-0001-9668-6366 et al. (3 more authors) (2019) Thermodynamic phase diagram of amyloid-β (16-22) peptide. Proceedings of the National Academy of Sciences of the United States of America, 116 (6). pp. 2091-2096. ISSN 0027-8424
Abstract
The aggregation of monomeric Aβ peptide into oligomers and amyloid fibrils in the mammalian brain is associated with Alzheimer’s disease. Insight into the thermodynamic stability of the Aβ peptide in different polymeric states is fundamental to defining and predicting the aggregation process. Experimental determination of Aβ thermodynamic behavior is challenging due to the transient nature of Aβ oligomers and the low peptide solubility. Furthermore, quantitative calculation of a thermodynamic phase diagram for a specific peptide requires extremely long computational times. Here, using a coarse-grained protein model, molecular dynamics simulations are performed to determine an equilibrium concentration and temperature phase diagram for the amyloidogenic peptide fragment, Aβ16-22. Our results reveal that the only thermodynamically stable phases are the solution phase and the macroscopic fibrillar phase, and that there also exists a hierarchy of metastable phases. The boundary line between the solution phase and fibril phase is found by calculating the temperature-dependent solubility of a macroscopic Aβ16-22 fibril consisting of an infinite number of β-sheet layers. To our knowledge, this is the first in silico determination of an equilibrium (solubility) thermodynamic phase diagram for a real amyloid-forming peptide. Furthermore, the in silico prediction of Aβ16-22 solubilities over the temperature range of 277-330K agrees well with fibrillation experiments and transmission electron microscopy measurements of the fibril morphologies formed. This in silico approach of predicting peptide solubility is also potentially useful for optimizing biopharmaceutical production and manufacturing nanofiber scaffolds for tissue engineering.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This article is protected by copyright. This is an author produced version of a paper published in Proceedings of the National Academy of Sciences of the United States of America. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | phase diagram; solubility; amyloid; protein aggregation; coarse-grained simulation |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Structural Molecular Biology (Leeds) The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Physical Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 17 Jan 2019 12:56 |
Last Modified: | 25 Jun 2023 21:40 |
Status: | Published |
Publisher: | National Academy of Sciences |
Identification Number: | 10.1073/pnas.1819592116 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:141149 |