Amyloid Evolution: Antiparallel replaced by Parallel

Abstract Several atomic structures have now been found for micrometer-scale amyloid fibrils or elongated microcrystals using a range of methods including NMR, electron microscopy and X-ray crystallography, with parallel β sheet appearing as the most common secondary structure. The etiology of amyloid disease, however, indicates nanometre-scale assemblies of only tens of peptides as significant agents of cytotoxicity and contagion. By combining solution X-ray with molecular dynamics we show that antiparallel structure dominates at the first stages of aggregation for a specific set of peptides, being replaced by parallel at large lengthscales only. This divergence in structure between small and large amyloid aggregates should inform future design of molecular therapeutics against nucleation or intercellular transmission of amyloid. Calculations, and an overview from the literature, argue that antiparallel order should be the first appearance of structure in many or most amyloid aggregation processes, regardless of the endpoint. Exceptions to this finding should exist, depending inevitably on the sequence and on solution conditions.