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A Small Molecule Stabilizes the Disordered Native State of the Alzheimer's Aβ Peptide.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Löhr, Thomas 
Kohlhoff, Kai 
Heller, Gabriella T 
Vendruscolo, Michele  ORCID logo  https://orcid.org/0000-0002-3616-1610

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.

Description

Keywords

Alzheimer’s disease, Aβ42 peptide, native state, small molecule, Alzheimer Disease, Amyloid beta-Peptides, Entropy, Humans, Intrinsically Disordered Proteins, Peptide Fragments

Journal Title

ACS Chem Neurosci

Conference Name

Journal ISSN

1948-7193
1948-7193

Volume Title

13

Publisher

American Chemical Society (ACS)