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Targeting the early steps of Aβ16–22 protofibril disassembly by N‐methylated inhibitors: A numerical study
Author(s) -
Chebaro Yassmine,
Derreumaux Philippe
Publication year - 2008
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.22254
Subject(s) - monomer , fibrillogenesis , molecular dynamics , fibril , chemistry , biophysics , intercalation (chemistry) , crystallography , stereochemistry , biochemistry , computational chemistry , biology , organic chemistry , polymer
Aggregation of the Aβ1–40/Aβ1–42 peptides is a key factor in Alzheimer's disease. Though the inhibitory effect of N‐methylated Aβ16–22 (mAβ16–22) peptides is well characterized in vitro , there is little information on how they disassemble full‐length Aβ fibrils or block fibril formation. Here, we report coarse‐grained implicit solvent molecular dynamics (MD) and replica exchange molecular dynamics (REMD) simulations on Aβ16–22 and mAβ16–22 monomers, and then a preformed six‐chain Aβ16–22 bilayer with either four copies of Aβ16–22 or four copies of mAβ16–22. Our simulations show that the effect of N‐methylation on mAβ16–22 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 μs help understand the first steps of Aβ16–22 protofibril disassembly by N‐methylated inhibitors. Notably, we find that mAβ16–22 preferentially interacts with Aβ16–22 by blocking both β‐sheet extension and lateral association of layers, but also by intercalation of the inhibitors allowing sequestration of Aβ16–22 peptides. This third binding mode is particularly appealing for blocking Aβ fibrillogenesis. Proteins 2009. © 2008 Wiley‐Liss, Inc.