Putative Pore Structures of Amyloid β 25-35 in Lipid Bilayers

The amyloid & beta; peptide aggregates to form extracellularplaquesin the brains of Alzheimer's disease patients. Certain of itsfragments have been found to have similar properties to those of thefull-length peptide. The best-studied of these is 25-35, which aggregatesinto fibrils, is toxic to neurons, and forms ion channels in syntheticlipid bilayers. Here, we investigate possible pore-forming structuresof oligomers of this peptide in a POPC/POPG membrane. We consideroctameric and decameric & beta;-barrels of different topology, strandorientation, and shear, evaluate their stability in an implicit membranemodel, and subject the best models to multimicrosecond all-atom moleculardynamics simulations. We find two decameric structures that are kineticallystable in membranes on this time scale: an imperfectly closed antiparallel & beta;-barrel with K28 in the pore lumen and a short parallel & beta;-barrelwith K28 toward the membrane interface. Both structures exhibit dehydratedgaps in the pore lumen, which are larger for the antiparallel barrel.Based on these results, the experimental cation selectivity, the dependenceof ion channel activity on voltage direction, and certain mutationdata, the parallel model seems more compatible with experimental data.