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

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 A beta 42 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 A beta 42 peptide remain disordered. This disordered binding mechanism involves enthalpically favorable local pi-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.

Automated summary

The stabilization of native states of proteins is a powerful drug discovery strategy. This study reveals that a small molecule can stabilize the intrinsically disordered state of the A beta 42 peptide associated with Alzheimer's disease through a disordered binding mechanism. This mechanism involves both enthalpic gain from local interactions and entropic gain from global effects.