Transient Aggregation-Prone States in Disordered Proteins as Therapeutic Targets: The Amyloid-β Case.

The amyloid-β (Aβ) peptide is an intrinsically disordered protein whose self-association into toxic oligomers underlies Alzheimer's disease. Because of its dynamic and heterogeneous nature, identifying the conformational states that nucleate aggregation remains a central challenge. In this work, we introduce a chemically interpretable descriptor of amyloidogenic propensity derived from self-docking analyses of conformational ensembles generated through temperature-replica exchange molecular dynamics (T-REMD) using different and complementary force fields. This descriptor classifies individual conformers within the generated ensembles according to their intrinsic aggregation tendency, enabling the identification of metastable, aggregation-prone states. The resulting ensembles reproduce experimental observables, and their classification based on amyloidogenic propensity provides a consistent structural basis for the rationalization and study of these metastable conformers. As a test, we demonstrate that the molecular chaperone DNAJB6, experimentally known to bind amyloidogenic conformations, preferentially interacts with aggregation-prone conformers, thus supporting both the proposed protocol and the consistency of the classification scheme. More broadly, this framework outlines a potentially generalizable strategy to identify metastable states in intrinsically disordered proteins as prospective pharmacological targets to help develop drugs or biomolecules capable of inhibiting the early stages of their aggregation.