The amyloid packing difference: A pairwise comparison metric for amyloid structures.

Because a given protein may adopt different amyloid protofilament folds, it has become necessary to compare pairs of amyloid structures of a given protein. This article describes the amyloid packing difference (APD), which quantifies the difference between amyloid structures as the percentage of residues involved in unique cross-β packing interactions or side-chain orientations. Clustering of α-synuclein folds on APD values recapitulates clustering based on structural superpositions. Known protofilament folds of the prion protein, tau, α-synuclein, TDP-43, or TAF15 from different neurodegenerative diseases have APD values above 20%, whereas structures that have been associated with the same disease have APD values below 40%. Different individuals with peripheral amyloidosis have antibody light-chain structures with APDs above 60%, whereas transthyretin filaments are strikingly similar, with APDs below 25%. These observations provide context for the interpretation of APD values in future structure comparisons.