Abstract
A potential mechanism of cytotoxicity attributed to Alzheimer's Aβ peptides postulates that their aggregation disrupts membrane structure causing uncontrollable permeation of Ca(2+) ions. To gain molecular insights into these processes, we have performed all-atom explicit solvent replica exchange with solute tempering molecular dynamics simulations probing aggregation of the naturally occurring Aβ fragment Aβ25-35 within the DMPC lipid bilayer. To compare the impact produced on the bilayer by Aβ25-35 oligomers and monomers, we used as a control our previous simulations, which explored binding of Aβ25-35 monomers to the same bilayer. We found that compared to monomeric species aggregation results in much deeper insertion of Aβ25-35 peptides into the bilayer hydrophobic core causing more pronounced disruption in its structure. Aβ25-35 peptides aggregate by incorporating monomer-like structures with stable C-terminal helix. As a result the Aβ25-35 dimer features unusual helix head-to-tail topology supported by a parallel off-registry interface. Such topology affords further growth of an aggregate by recruiting additional peptides. Free energy landscape reveals that inserted dimers represent the dominant equilibrium state augmented by two metastable states associated with surface bound dimers and inserted monomers. Using the free energy landscape we propose the pathway of Aβ25-35 binding, aggregation, and insertion into the lipid bilayer.