Conformational Ensemble and Polymorphism of the All-Atom Alzheimer’s Aβ37–42 Amyloid Peptide Oligomers

Abstract

Although the Aβ(37-42) peptide has two opposite terminal charges, counterintuitively its current fibril amyloid structure reveals in register parallel β-strands, as formed by the full length Aβ peptide. In this study, we carried out a replica exchange molecular dynamics simulation of 16 all-atom Aβ(37-42) peptides in explicit water starting from randomized and dispersed chains. The extensive conformational sampling (48 replicas, 460 ns/replica) with a total simulation time of 23 μs allows us to obtain a full picture on the equilibrium conformational distribution of oligomers and β-sheet sizes and gain some insights into the oligomerization process at 300 K. At the peptide concentration of 12 mM, self-assembly is described by the condensation-polymerization mechanism with conversion from micelle-like to high β-sheet structures. At equilibrium, the oligomer distribution consists of large aggregates and free monomers, representing 70% and 25% of all species, respectively. Though the formation/dissociation of β-strand is high, the population of 4-5 fully parallel β-strands, consistent with the arrangement in the current fibril, is marginal and that of 4-5 fully antiparallel β-strands, consistent with amyloid polymorphism, is non-negligible. However, the system adopts essentially mixed parallel/antiparallel β-strands. This indicates that a system of 16 Aβ(37-42) chains in explicit solvent still does not form more stable species that will irreversibly grow to a fibril, independently of polymorphism. Our results also suggest that the Aβ(37-42) fibril may display packing polymorphism with antiparallel β-strands, in addition to the experimentally observed in register parallel β-strands.