From Aβ Filament to Fibril: Molecular Mechanism of Surface-Activated Secondary Nucleation from All-Atom MD Simulations

• DOI: 10.1021/acs.jpcb.6b10189
• Publication Date: 2016-12-19T20:24:55Z
• Authors: Nadine Schwierz; Christina V. Frost; Phillip L. Geissler; Martin Zacharias
• Keywords: Elongation

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