Dimerization of Aβ40 inside dipalmitoylphosphatidylcholine bilayer and its effect on bilayer integrity: Atomistic simulation at three temperatures

Amyloid-beta (A beta) protein is related to Alzheimer disease (AD), and various experiments have shown that oligomers as small as dimers are cytotoxic. Recent studies have concluded that interactions of A beta with neuronal cell membranes lead to disruption of membrane integrity and toxicity and they play a key role in the development of AD. Molecular dynamics (MD) simulations have been used to investigate A beta in aqueous solution and membranes. We have previously studied monomeric A beta 40 embedded in dipalmitoylphosphatidylcholine (DPPC) membrane using MD simulations. Here, we explore interactions of two A beta 40 peptides in DPPC bilayer and its consequences on dimer distribution in a lipid bilayer and on the secondary structure of the peptides. We explored that N-terminals played an important role in dimeric A beta peptide aggregations and A beta-bilayer interactions, while C-terminals bound peptides to bilayer like anchors. We did not observe exiting of peptides in our simulations although we observed insertion of peptides into the core of bilayer in some of our simulations. So it seems that the presence of A beta on membrane surface increases its aggregation rate, and as diffusion occurs in two dimensions, it can increase the probability of interpeptide interactions. We found that dimeric A beta, like monomeric one, had the ability to cause structural destabilization of DPPC membrane, which in turn might ultimately lead to cell death in an in vivo system. This information could have important implications for understanding the affinity of A beta oligomers (here dimer) for membranes and the mechanism of A beta oligomer toxicity in AD.