An Original Monomer Sampling from a Ready-Made Aβ42 NMR Fibril Suggests a Turn-β-Strand Synergetic Seeding Mechanism

Aggregation of amyloid beta (A beta) is a central step of Alzheimer's disease. A beta 42 monomers are building blocks in the formation of both on pathway intermediate structures and off pathway oligomers. How to sample an A beta monomer becomes a problem however due to the instinct of A beta 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 A beta 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 beta-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 beta 1-seeding dynamics characteristic is observed probably due to far insufficient conformation transition in the limited simulation time. Two dynamics characteristics of A beta 42 folding observed experimentally, that either beta 1 region or beta 2 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-beta-strand synergetic seeding mechanism of aggregation is first proposed based on the trajectory analyses on the four regions of A beta 42 chain.