A Multi-scale Study of β-Amyloid Wild-Type and Mutant Peptides: Monomers, Oligomers, Fibrils

Abstract

Alzheimer's Disease affects millions of people and is becoming more prevalent. It is believed to be caused by aggregates of β-amyloid (Aβ) peptides. The end-points of aggregation are amyloid fibrils, though is it widely believed that soluble, oligomeric precursors of the fibrils are the more important neurotoxins. Aβ is known to form highly polymorphic fibrils, with many mutant forms observed in patients. Some mutants, such as the Iowa (D23N) and the Osaka (E22Δ), are known to have increased neurotoxicity and faster aggregation in relation to wild-type peptides. To investigate the differences between wild-type and mutant Aβ-peptides, we modeled their behavior at four levels: monomer, oligomer, finite and infinite fibrils; using long all atom molecular dynamics simulations. The two wild-type fibril structures in our simulations were pdb entries 2LMN and 2LMP (having two- and three-stacks), the Osaka mutant structure was 2MVX (having two-stacks) and the Iowa mutant structures were 2LNQ and 2MPZ (having one- and three-stacks). The Osaka mutant demonstrated the most structural stability evident from its higher average β-content (that is known experimentally to be strongly correlated to stability in amyloid fibrils). We attribute this to strong inter-backbone hydrogen-bond network and a strong salt-bridge between residues E3-R28 unique to the Osaka mutant. We also observed a larger number of sodium ions accumulated on the interior pockets of the Osaka-mutant fibril. These can explain the very fast aggregation of the Osaka mutant and possibly its higher neurotoxicity. The Iowa mutant structure (2MPZ) and wild-type structure (2LMP) had similar structural stability as well as aqueous-pore like behavior, which might disrupt cell function if inserted through a membrane. The one-stack Iowa mutant showed the least structural stability that may imply the need for more than one-stack for a strong fibril integrity.

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