Amyloid A¦Â25-35 Fragment Oligomers And Popg Bilayers By Molecular Dynamics Simulation

Alzheimer's disease, also known as senile dementia, had already 26.6 million cases all over the world in 2006, and it's estimated that in 2050 one out of 85 will suffer Alzheimer's disease, which severely threaten the human health. In experiment, diseases such as Alzheimer's disease, Dementiawith Lewybodies (DLB), Inclusion body myositis are closely related with amyloid fibril deposition, among which the main component of Alzheimer's disease's deposition is Aβfragment. Now researches about pathogenesis of Alzheimer's disease mainly focus on the aggregation of Aβpeptide and the interactions between Aβpeptide and other molecules in cell.Aβ25-35, a proteolytic fragment of the Alzheimer amyloid beta (Aβ) peptide, is physiologically produced in the brains of Alzheimer's patients and retains the neurotoxicity of its full-length counterpart. The formation of ion channels in membranes has been reported as one of the mechanism responsible for Aβ25-35 toxicity. In addition, it has been proposed that channel might be formed by the aggregation of Aβ25-35 in membranes into aβ-barrel structure. However, the structure ofβ-barrel and its perturbation on the ordering of lipid bilayer at atomic level are yet to be determined. In this study, we investigate the interactions of two different preformed Aβ25-35β-barrels with negatively charged POPG membrane using all-atom molecular dynamics simulations. The Aβ25-35β-barrels consist of eight mixed-parallel/antiparallelβ-strands with the positively charged side chains of Lys located in its outer side (taken from our previous study, labeled as Barrel A) or in its inner side (Barrel B). Simulations are performed by employing configurations where the barrels are fully or partially inserted into the bilayer. When Aβ25-35β-barrel is fully inserted into the bilayer, Barrel B causes membrane leakage by forming nanometer-sized hydrophilic toroidal pore, while Barrel A has much less perturbation effect on the lipid bilayer. Partial insertion of the Aβ25-35β-barrel in the bilayer results in a preference to stay in the membrane for Barrel B and a tendency to exit the lipid bilayer for Barrel A. These results suggest thatβ-barrel-like oligomer with Lys side chain in its inner side is a possible Aβ25-35 channel model leading to nonspecific membrane leakage.