Targeting the early steps of Abeta16-22 protofibril disassembly by N-methylated inhibitors: a numerical study.
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.
Chebaro
Yassmine
Y
Laboratoire de Biochimie Théorique, UPR 9080 CNRS, Institut de Biologie, Physico Chimique et Université Paris 7 Denis Diderot, 13 rue Pierre et Marie Curie, Paris 75005, France.
Derreumaux
Philippe
P
D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D003198:Computer Simulation; D006801:Humans; D008745:Methylation; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary
D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C417223:amyloid beta-protein (16-22)