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

Abstract

The early events in the aggregation of the intrinsically disordered peptide, A{beta}, involve transitions from the disordered lowest free energy ground state to assembly-competent states. Are the finger-prints 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 A{beta}42 compared to A{beta}40 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 SOP-IDP model of A{beta}40 and A{beta}42. 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 (N*) states, which resemble the monomers in the fibril structure. The free energy gap between the ground (RC) and the N* states of A{beta}42 peptide is smaller than for A{beta}40. 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 A{beta}42 relative to A{beta}40. The N* concept accounts for fibril polymorphs, leading to the prediction that the less stable N* state of A{beta}42, encoding for the U-bend fibril, should form earlier than the structure with the S-bend topology, which is in accord with the Ostwalds rule rationalizing crystal polymorph formation. Significance StatementAlzheimers disease (AD), a rampant neurodegenerative disorder, is caused by the accumulation of pathological aggregates, primarily composed of the two isoforms A{beta}40 and A{beta}42. Experiments have shown that A{beta}42 is more aggregation-prone compared to A{beta}40. However, the molecular origin of this apparent anomaly remains elusive. Here, we provide a microscopic basis for the different aggregation rates in terms of the distinct populations of high free energy excited fibril-like states (N*) that are encoded in the monomer spectra. The N* theory explains the emergence of fibril polymorphs, and predicts the relative kinetic stabilities of A{beta}42 fibrils using Ostwalds rule of stages. Our work shows that sequence-specific conformational heterogeneity of the monomer ensembles provides important cues for understanding protein aggregation.