The amyloid packing difference: a pairwise comparison metric for amyloid structures

Abstract

Several proteins from the human proteome have been observed to adopt multiple distinct amyloid filaments, and specific protofilament folds are associated with different diseases. Thereby, it has become necessary to compare pairs of amyloid structures of a given protein. This paper describes the amyloid packing difference (APD), which quantifies the difference between such a pair as the percentage of residues that are involved in unique cross-{beta} packing interactions or that have different side chain orientations relative to the {beta}-strands. Clustering of -synuclein protofilament folds on pairwise APD values recapitulates previously reported clustering based on structural superpositions. Any pair of known protofilament folds of the prion protein, tau, -synuclein, TDP-43 or TAF15 from different neurodegenerative diseases have APD values above 20%, whereas all pairs of structures that have been associated with the same disease have APD values below 40%. Structures of antibody light chain from different individuals with systemic amyloidosis differ from each by APDs above 60%, whereas structures of transthyretin filaments from different individuals are strikingly similar, with APDs below 25%. These observations provide context for the interpretation of APD values in future structure comparisons.