Comparative Study of Polymorphous Alzheimer's Aβ(1-40) Amyloid Nanofibrils and Microfibers

The class of amyloid protein materials has been associated with severe degenerative diseases, such as Parkinson's disease, Alzheimer's disease and type II diabetes. Moreover, they represent an intriguing class of protein molecules that show exceptional strength, sturdiness and elasticity. However, physical models that explain the structural basis of these properties remain largely elusive. This is partly due to the fact that structural models of microscale amyloid fibrils remain unknown, preventing us from pursuing bottom-up studies to describe the link between their hierarchical structure and physical properties. Here we focus on the p-amyloid peptide A beta(1-40), which is associated with Alzheimer's disease. Earlier experimental studies suggest that this amyloid fibril arranges in both double and triple layered beta-sheet structures, leading to twofold and threefold morphologies. The resulting structures are stabilized by a hydrophobic core and interprotein H-bond networks. Here we identify the atomistic coordinates of both twofold and threefold morphologies, providing a structural fiber model with lengths of hundreds of nanometers. We present a systematic comparison between the two morphologies, including energetic properties, structural changes and H-bonding patterns, for varying fibril lengths. Our results suggest that the double layered morphology is more stable than the threefold morphology. The model described here predicts the formation of twisted amyloid microfibers with a periodicity of approximate to 133 nm and approximate to 82 nm, for the twofold and threefold structures, respectively. The approach proposed here makes a direct connection from the atomistic to the mesoscale level, provides a link between the fibril geometry, the chemical interactions and the final more stable configuration, and resolves the issue of missing atomistic structures for long amyloid fibers.