A Small Molecule Stabilizes the Disordered Native State of the Alzheimer's Aβ Peptide.
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Publication Date
2022-06-15Journal Title
ACS Chem Neurosci
ISSN
1948-7193
Publisher
American Chemical Society (ACS)
Volume
13
Issue
12
Pages
1738-1745
Language
eng
Type
Article
This Version
VoR
Metadata
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Löhr, T., Kohlhoff, K., Heller, G. T., Camilloni, C., & Vendruscolo, M. (2022). A Small Molecule Stabilizes the Disordered Native State of the Alzheimer's Aβ Peptide.. ACS Chem Neurosci, 13 (12), 1738-1745. https://doi.org/10.1021/acschemneuro.2c00116
Abstract
The stabilization of native states of proteins is a powerful drug discovery strategy. It is still unclear, however, whether this approach can be applied to intrinsically disordered proteins. Here, we report a small molecule that stabilizes the native state of the Aβ42 peptide, an intrinsically disordered protein fragment associated with Alzheimer's disease. We show that this stabilization takes place by a disordered binding mechanism, in which both the small molecule and the Aβ42 peptide remain disordered. This disordered binding mechanism involves enthalpically favorable local π-stacking interactions coupled with entropically advantageous global effects. These results indicate that small molecules can stabilize disordered proteins in their native states through transient non-specific interactions that provide enthalpic gain while simultaneously increasing the conformational entropy of the proteins.
Keywords
Alzheimer’s disease, Small Molecule, Native State, Aβ42 Peptide, Humans, Alzheimer Disease, Peptide Fragments, Entropy, Amyloid beta-Peptides, Intrinsically Disordered Proteins
Identifiers
PMC9204762, 35649268
External DOI: https://doi.org/10.1021/acschemneuro.2c00116
This record's URL: https://www.repository.cam.ac.uk/handle/1810/338712
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