How the amyloid-β peptide and membranes affect each other: An extensive simulation study

The etiology of Alzheimer's disease is thought to be linked to interactions between amyloid-beta (A beta) and neural cell membranes, causing membrane disruption and increased ion conductance. The effects of A beta on lipid behavior have been characterized experimentally, but structural and causal details are lacking. We used atomistic molecular dynamics simulations totaling over 6 mu s in simulation time to investigate the behavior of A beta(42) in zwitterionic and anionic lipid bilayers. We simulated transmembrane beta-sheets (monomer and tetramer) resulting from a global optimization study and a helical structure obtained from an NMR study. In all simulations A beta(42) remained embedded in the bilayer. It was found that the surface charge and the lipid tail type are determinants for transmembrane stability of A beta(42) with zwitterionic surfaces and unsaturated lipids promoting stability. From the considered structures, the beta-sheet tetramer is most stable as a result of interpeptide interactions. We performed an in-depth analysis of the translocation of water in the A beta(42)-bilayer systems. We observed that this process is generally fast (within a few nanoseconds) yet generally slower than in the peptide-free bilayers. It is mainly governed by the lipid type, simulation temperature and A beta(42) conformation. The rate limiting step is the permeation through the hydrophobic core, where interactions between A beta(42) and permeating H2O molecules slow the translocation process. The beta-sheet tetramer allows more water molecules to pass through the bilayer compared to monomeric A beta, allowing us to conclude that the experimentally observed permeabilization of membranes must be due to membrane-bound A beta oligomers, and not monomers. (C) 2012 Elsevier B.V. All rights reserved.