Monomer adds to preformed structured oligomers of Aβ-peptides by a two-stage dock–lock mechanism

Nonfibrillar soluble oligomers, which are intermediates in the transition from monomers to amyloid fibrils, may be the toxic species in Alzheimer's disease. To monitor the early events that direct assembly of amyloidogenic peptides we probe the dynamics of formation of (Aβ16–22)n by adding a monomer to a preformed (Aβ16–22)n−1 (n = 4–6) oligomer in which the peptides are arranged in an antiparallel β-sheet conformation. All atom molecular dynamics simulations in water and multiple long trajectories, for a cumulative time of 6.9 μs, show that the oligomer grows by a two-stage dock–lock mechanism. The largest conformational change in the added disordered monomer occurs during the rapid (≈50 ns) first dock stage in which the β-strand content of the monomer increases substantially from a low initial value. In the second slow-lock phase, the monomer rearranges to form in register antiparallel structures. Surprisingly, the mobile structured oligomers undergo large conformational changes in order to accommodate the added monomer. The time needed to incorporate the monomer into the fluid-like oligomer grows even when n = 6, which suggests that the critical nucleus size must exceed six. Stable antiparallel structure formation exceeds hundreds of nanoseconds even though frequent interpeptide collisions occur at elevated monomer concentrations used in the simulations. The dock–lock mechanism should be a generic mechanism for growth of oligomers of amyloidogenic peptides.

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