Targeting the early steps of Aβ16–22 protofibril disassembly by N‐methylated inhibitors: A numerical study

Abstract

Aggregation of the Abeta1-40/Abeta1-42 peptides is a key factor in Alzheimer's disease. Though the inhibitory effect of N-methylated Abeta16-22 (mAbeta16-22) peptides is well characterized in vitro, there is little information on how they disassemble full-length Abeta fibrils or block fibril formation. Here, we report coarse-grained implicit solvent molecular dynamics (MD) and replica exchange molecular dynamics (REMD) simulations on Abeta16-22 and mAbeta16-22 monomers, and then a preformed six-chain Abeta16-22 bilayer with either four copies of Abeta16-22 or four copies of mAbeta16-22. Our simulations show that the effect of N-methylation on mAbeta16-22 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 micros help understand the first steps of Abeta16-22 protofibril disassembly by N-methylated inhibitors. Notably, we find that mAbeta16-22 preferentially interacts with Abeta16-22 by blocking both beta-sheet extension and lateral association of layers, but also by intercalation of the inhibitors allowing sequestration of Abeta16-22 peptides. This third binding mode is particularly appealing for blocking Abeta fibrillogenesis.

Structure−Activity Relationships in Peptide Modulators of β-Amyloid Protein Aggregation: Variation in α,α-Disubstitution Results in Altered Aggregate Size and Morphology

“…Molecular dynamic simulations have been employed to study the mechanism of how these mitigators interact and disassemble fibrils (80,83,84). Recently, Yassmine et al showed through simulation the disassembly of Aβ [16][17][18][19][20][21][22] protofibrils by N-methylated inhibitors (85). They reported that Nmethylated inhibitors interact with the protofibril by both lateral and longitudinal association, thereby disrupting the β-sheet extension and its lateral association into layers.…”

Inhibition of protein aggregation and amyloid formation by small molecules

“…BAF31 significantly reduces toxicity in cells by preventing fibril fragmentation [23 ]. Simulations revealed however that inhibitors can block lateral association of layers [24], suggesting that BAF31 may also prevent protofibrils association. In addition, the complex and highly dynamical behavior of an inhibitor on human amylin fibrils was revealed using isotope-edited IR, indicating the limitations of the static amyloid fibrils/inhibitor structure [25 ].…”

Communication: Simulated tempering with fast on-the-fly weight determination

“…21 Oligomers of amyloid peptides are of therapeutic interest since they are the most toxic species in human neurodegenerative diseases. 22 For both systems, we chose the T range of 280-500 K spaced exponentially into 20 values. Starting from fully extended conformations for both systems and well separated peptides for the trimer, the ST simulations were performed for 400 ns using an integration step of 1.5 fs and the Langevin thermostat.…”