Theory of concentric β-barrel structures: models of amyloid beta 42 oligomers, annular protofibrils, and transmembrane channels

Abstract

Amyloid beta (A{beta}) peptides are a major contributor to Alzheimers disease. Previously, our group proposed molecular models of A{beta}42 hexamers with two concentric antiparallel {beta}-barrels that act as seeds from which dodecamers, octadecamers, both smooth and beaded annular protofibrils, and transmembrane channels form. Since then, numerous aspects of our models have been supported by experimental findings. Here we develop a more extensive range of models to be consistent with dimensions of assemblies observed in electron microscopy images of annular protofibrils and transmembrane assemblies. These models have the following features: Dodecamers with 2-concentric {beta}-barrels are the major components of beaded annular protofibrils (bAPFs). These beads merge to form smooth annular protofibrils (sAPFs) that have three or four concentric {beta}-barrels. Channels form from two to nine hexamers. Antiparallel C-terminus S3 segments form an outer transmembrane {beta}-barrel. Half of the monomers of vertically asymmetric 12mer to 36mer channels form parallel transmembrane S2 {beta}-barrels, and S1-S2 (N-terminus and middle) segments of the other half of the monomers form aqueous domains on the cis side of the membrane. Unit cells of 42-54mers have two more transmembrane S2 segments, with four concentric {beta}-barrels in the transmembrane region and two concentric {beta}-barrels on the cis side of the membrane.