Structural and thermodynamic classification of amyloid polymorphs

Over 500 amyloid structures have been solved to date to near-atomic resolution. This has highlighted an enormous diversity of fibril structures conforming to the canonical cross-β amyloid fold. Using α-synuclein and tau amyloid structures as models, we show that they can be hierarchically clustered into topologically distinct fold families. Despite their different topologies, fibrils display remarkably similar energy profiles, as determined by FoldX, with the same regions providing stability among different polymorphs. We found that the regions that stabilize the amyloid core pair in different ways to generate distinct topologies. The results provide a framework to classify newly solved fibril structures as belonging to an existing class or forming a new topological cross-β fold. Furthermore, the analysis facilitates comparisons between fibrils found in disease and those formed in vitro, including their nearest structural neighbors. The workflow has been automated, enabling users to interrogate new amyloid structures as they emerge.