Non-micelle-like Amyloid Aggregate Stabilizes Amyloid β (1-42) Growth Nuclei Formation

Protein aggregate formations are essential processes to regulate biochemical networks in the cell, while anomalously formed aggregates such as amyloid fibrils cause serious neuronal diseases. It has been discussed for a quarter century that protein crowding milieus, such as micelle-like aggregates, promote the formation of growth nuclei, fibril-growth competent aggregates which trigger rapid growth of pathogenic amyloid fibrils, but the mechanisms are still elusive, in particular at microscopic level. In this study, we examined the long-standing problem by employing atomistic molecular dynamics simulations for amyloid β(1-42) (Aβ 42 ), the paradigmatic amyloid-forming peptide. First, we constructed an atomistic model of Aβ 42 growth nuclei in Aβ 42 aggregate milieu, the pentameric Aβ 42 protomer dimer surrounded by 40 Aβ 42 monomers. Next, we simulated Aβ 42 monomer dissociation from the Aβ 42 growth nuclei and examined the effect of Aβ 42 aggregate milieu on the process. Aβ 42 aggregates spatially restrict Aβ 42 monomer dissociation pathways, while such spatial restriction itself does not significantly suppress Aβ 42 monomer dissociation from the growth nuclei. Rather, Aβ 42 aggregate milieus thermodynamically stabilize an Aβ 42 monomer binding to the growth edge by making atomic contacts with the monomer and contributes to stable formation of growth nuclei. A part of the aggregate milieu anchors dissociating monomer to the remaining part of growth nuclei, suggesting cooperative suppression of Aβ 42 monomer dissociation from Aβ 42 growth nuclei. Since the Aβ 42 aggregate milieu does not take a micelle-like configuration, we here discuss a new mechanism for stable formation of Aβ 42 growth nuclei in the presence of aggregate milieu.