Differences in the free energies between the excited states of Aβ40 and Aβ42 monomers encode their aggregation propensities.

The early events in the aggregation of the intrinsically disordered peptide, amyloid-β (Aβ), involve transitions from the disordered free energy ground state to assembly-competent states. Are the fingerprints of order found in the amyloid fibrils encoded in the conformations that the monomers access at equilibrium? If so, could the enhanced aggregation rate of Aβ42 compared to Aβ40 be rationalized from the sparsely populated high free energy states of the monomers? Here, we answer these questions in the affirmative using coarse-grained simulations of the self-organized polymer-intrinsically disordered protein (SOP-IDP) model of Aβ40 and Aβ42. Although both the peptides have practically identical ensemble-averaged properties, characteristic of random coils (RCs), the conformational ensembles of the two monomers exhibit sequence-specific heterogeneity. Hierarchical clustering of conformations reveals that both the peptides populate high free energy aggregation-prone ([Formula: see text]) states, which resemble the monomers in the fibril structure. The free energy gap between the ground (RC) and the [Formula: see text] states of Aβ42 peptide is smaller than that for Aβ40. By relating the populations of excited states of the two peptides to the fibril formation time scales using an empirical formula, we explain nearly quantitatively the faster aggregation rate of Aβ42 relative to Aβ40. The [Formula: see text] concept accounts for fibril polymorphs, leading to the prediction that the less stable [Formula: see text] state of Aβ42, encoding for the U-bend fibril, should form earlier than the structure with the S-bend topology, which is in accord with Ostwald's rule rationalizing crystal polymorph formation.