Varied Probability of Staying Collapsed/Extended at the Conformational Equilibrium of Monomeric Aβ(40) and Aβ(42)

In present study, we set out to investigate the conformation dynamics of Aβ(40) and Aβ(42) through exploring the impact of intra-molecular interactions on conformation dynamics using equilibrium molecular dynamics simulations. Our 40 microsecond-scale simulations reveal heterogeneous conformation ensembles of Aβ(40) and Aβ(42) that encompass ~35% β-strand and ~60% unstructured coils. Two conformational states were identified in both alloforms: a collapsed state (CS) that resembles the structural motif of face-to-face hydrophobic clustering in amyloid fibrils, and an extended state (ES) that features the structural characteristics of anti-parallel β-sheets in amyloid oligomers. In Aβ(40), the C-terminus remains unstructured and rarely interacts with other parts, thereof the hydrophobic clustering is in loose contact and the peptide assumes ES with high probability. In contrast, the C-terminus of Aβ(42) adopts a β-strand structure that strongly interacts with segments E3-R5 and V18-A21. The active association leads to a more compact hydrophobic collapse and refrain the alloform from ES. Based on the structural characterization, we propose that the fibril and oligomer assembly pathways could respectively take off from CS and ES, and their aggregation propensity may be governed by the probability of visiting the corresponding conformational states at the equilibrium.