Targeting the early steps of Aβ 16-22 protofibril disassembly by N-methylated inhibitors: A numerical study

Aggregation of the A beta 1-40/A beta 1-42 peptides is a key factor in Alzheimer's disease. Though the inhibitory effect of N-methylated A beta 16-22 (mA beta 16-22) peptides is well characterized in vitro, there is little information on how they disassemble full-length A beta fibrils or block fibril formation. Here, we report coarse-grained implicit solvent molecular dynamics (MD) and replica exchange molecular dynamics (REMD) simulations on A beta 16-22 and mA beta 16-22 monomers, and then a preformed six-chain A beta 16-22 bilayer with either four copies of A beta 16-22 or four copies of mA beta 16-22. Our simulations show that the effect of N-methylation on mA beta 16-22 monomer is to reduce the density of compact forms. While 100 ns MD trajectories do not reveal any significant differences between the two ten-chain systems, the REMD simulations totaling 1 mu s help understand the first steps of A beta 16-22 protofibril disassembly by N-methylated inhibitors. Notably, we find that mA beta 16-22 preferentially interacts with A beta 16-22 by blocking both P-sheet extension and lateral association of layers, but also by intercalation of the inhibitors allowing sequestration of A beta 16-22 peptides. This third binding mode is particularly appealing for blocking A beta fibrillogenesis.