Molecular modeling of the core of Aβ amyloid fibrils

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Abstract
Amyloid fibrils, a key pathological feature of Alzheimer's disease (AD) and other amyloidosis implicated in neurodegeneration, have a characteristic cross‐β structure. Here we present a structural model for the core of amyloid fibrils formed by the Aβ peptide using computational approaches and experimental data. Aβ(15–36) was threaded against the parallel β‐helical proteins. Our multi‐layer model was constructed using the top scoring template 1lxa, a left‐handed parallel β‐helical protein. This six‐rung helical model has in‐register repeats of the Aβ(15–36) sequence. Each rung has three β‐strands separated by two turns. The model was tested using molecular dynamics simulations in explicit water, and is in good agreement with a number of experimental observations. In addition, a model based on right‐handed helical proteins is also described. The core structural model described here might serve as the building block of the Aβ(1–40) amyloid fibril as well as some other amyloid fibrils. Proteins 2004.