An original monomer sampling from a ready‐made Aβ42 NMR fibril suggested a turn‐β‐strand synergetic seeding mechanism

: Aggregation of amyloid beta (Aβ) is a central step of Alzheimer's disease. Aβ42 monomers are building blocks in the formation of both "on pathway" intermediate structures and "off pathway" oligomers. How to sample an Aβ monomer becomes a problem however due to the instinct of Aβ high flexibility and diversity as well as aggregation propensity. Currently, (1) most samplings focus on either the ready-made helix-rich 1Z0Q/1IYT NMR structure, or the completely extended conformation, but (2) few on a ready-made Aβ NMR fibril (i. e., 2BEG). Here we compare the simulation results from sampling in scheme (1) with that in scheme (2), and find that the coil and β-sheet contents in the 1Z0Q-sampled system are comparable to the counterparts in the 2BEG-sampled system, but with a large difference in simulation time and dynamics character. 1Z0Q-sampled system not only takes several times longer than the 2BEG-sampled one, and only β1-seeding dynamics characteristic is observed probably due to far insufficient conformation transition in the limited simulation time. Two dynamics characteristics of Aβ42 folding observed experimentally, that either β1 region or β2 region aggregates first, reproduce in the present simulations for 2BEG-sampled system however, suggesting a preferential sampling in the future simulation. In addition, a turn-β-strand synergetic seeding mechanism of aggregation is first proposed based on the trajectory analyses on the four regions of Aβ42 chain.