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

• DOI: 10.1021/acschemneuro.2c00116
• Publication Date: 2022-06-01T21:13:46Z
• Authors: Thomas Löhr; Kai Kohlhoff; Gabriella T. Heller; Carlo Camilloni; Michele Vendruscolo
• Keywords: Intrinsically Disordered Proteins

The stabilization of native states proteins is a powerful drug discovery strategy. It still unclear, however, whether this approach can be applied to intrinsically disordered proteins. Here, we report small molecule that stabilizes the state Aβ42 peptide, an protein fragment associated with Alzheimer's disease. We show takes place by binding mechanism, in which both and peptide remain disordered. This mechanism involves enthalpically favorable local π-stacking interactions coupled entropically advantageous global effects. These results indicate molecules stabilize their through transient non-specific provide enthalpic gain while simultaneously increasing conformational entropy