A Small Molecule Stabilizes the Disordered Native State of the Alzheimer's Aβ Peptide.
Heller, Gabriella T
ACS Chem Neurosci
American Chemical Society (ACS)
MetadataShow full item record
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
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.
Alzheimer’s disease, Aβ42 peptide, native state, small molecule, Alzheimer Disease, Amyloid beta-Peptides, Entropy, Humans, Intrinsically Disordered Proteins, Peptide Fragments
External DOI: https://doi.org/10.1021/acschemneuro.2c00116
This record's URL: https://www.repository.cam.ac.uk/handle/1810/338712
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/
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