A Small Molecule Stabilizes the Disordered Native State of the Alzheimer's Aβ Peptide.
ACS Chem Neurosci
American Chemical Society (ACS)
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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
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, Small Molecule, Native State, Aβ42 Peptide, Humans, Alzheimer Disease, Peptide Fragments, Entropy, Amyloid beta-Peptides, Intrinsically Disordered Proteins
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/