jp6b10189_si_001.pdf (1.06 MB)
From Aβ Filament to Fibril: Molecular Mechanism of Surface-Activated Secondary Nucleation from All-Atom MD Simulations
journal contribution
posted on 2016-12-19, 00:00 authored by Nadine Schwierz, Christina V. Frost, Phillip L. Geissler, Martin ZachariasSecondary
nucleation pathways in which existing amyloid fibrils
catalyze the formation of new aggregates and neurotoxic oligomers
are of immediate importance for the onset and progression of Alzheimer’s
disease. Here, we apply extensive all-atom molecular dynamics simulations
in explicit water to study surface-activated secondary nucleation
pathways at the extended lateral β-sheet surface of a preformed
Aβ9–40 filament. Calculation of free-energy
profiles allows us to determine binding free energies and conformational
intermediates for nucleation complexes consisting of 1–4 Aβ
peptides. In addition, we combine the free-energy profiles with position-dependent
diffusion profiles to extract complementary kinetic information and
macroscopic growth rates. Single monomers bind to the β-sheet
surface in a disordered, hydrophobically collapsed conformation, whereas
dimers and larger oligomers can retain a cross-β conformation
resembling a more ordered fibril structure. The association processes
during secondary nucleation follow a dock/lock mechanism consisting
of a fast initial encounter phase (docking) and a slow structural
rearrangement phase (locking). The major driving forces for surface-activated
secondary nucleation are the release of a large number of hydration
water molecules and the formation of hydrophobic interface contacts,
the latter being in contrast to the elongation process at filament
tips, which is dominated by the formation of stable and highly specific
interface hydrogen bonds. The calculated binding free energies and
the association rates for the attachment of Aβ monomers and
oligomers to the extended lateral β-sheet surface of the filament
seed are higher compared to those for
elongation at the filament tips, indicating that secondary nucleation
pathways can become important once a critical concentration of filaments
has formed.