Beta-barrel models of soluble amyloid beta oligomers and annular protofibrils

Both soluble and membrane-bound prefibrillar assemblies of Abeta (A beta) peptides have been associated with Alzheimer's disease (AD). The size and nature of these assemblies vary greatly and are affected by many factors. Here, we present models of soluble hexameric assemblies of A beta 42 and suggest how they can lead to larger assemblies and eventually to fibrils. The common element in most of these assemblies is a six-stranded beta-barrel formed by the last third of A beta 42, which is composed of hydrophobic residues and glycines. The hydrophobic core beta-barrels of the hexameric models are shielded from water by the N-terminus and central segments. These more hydrophilic segments were modeled to have either predominantly beta or predominantly alpha secondary structure. Molecular dynamics simulations were performed to analyze stabilities of the models. The hexameric models were used as starting points from which larger soluble assemblies of 12 and 36 subunits were modeled. These models were developed to be consistent with numerous experimental results.