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) (Aβ42), the paradigmatic amyloid-forming peptide. First, we constructed an atomistic model of Aβ42 growth nuclei in Aβ42 aggregate milieu, the pentameric Aβ42 protomer dimer surrounded by 40 Aβ42 monomers. Next, we simulated Aβ42 monomer dissociation from the Aβ42 growth nuclei and examined the effect of Aβ42 aggregate milieu on the process. Aβ42 aggregates spatially restrict Aβ42 monomer dissociation pathways, while such spatial restriction itself does not significantly suppress Aβ42 monomer dissociation from the growth nuclei. Rather, Aβ42 aggregate milieus thermodynamically stabilize an Aβ42 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 Aβ42 monomer dissociation from Aβ42 growth nuclei. Since the Aβ42 aggregate milieu does not take a micelle-like configuration, we here discuss a new mechanism for stable formation of Aβ42 growth nuclei in the presence of aggregate milieu.