De novo aggregation of Alzheimer's A?25-35 peptides in a lipid bilayer.

ABSTRACT: A potential mechanism of cytotoxicity attributed to Alzheimer's A? peptides postulates that their aggregation disrupts membrane structure causing uncontrollable permeation of Ca²⁺ 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 A? fragment A?25-35 within the DMPC lipid bilayer. To compare the impact produced on the bilayer by A?25-35 oligomers and monomers, we used as a control our previous simulations, which explored binding of A?25-35 monomers to the same bilayer. We found that compared to monomeric species aggregation results in much deeper insertion of A?25-35 peptides into the bilayer hydrophobic core causing more pronounced disruption in its structure. A?25-35 peptides aggregate by incorporating monomer-like structures with stable C-terminal helix. As a result the A?25-35 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 A?25-35 binding, aggregation, and insertion into the lipid bilayer.

SUBMITTER: Smith AK 

PROVIDER: S-EPMC6509337 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature