Energetics Underlying Twist Polymorphisms in Amyloid Fibrils

Amyloid fibrils are highly ordered protein aggregates associated with more than 40 human diseases. The exact conditions under which the fibrils are grown determine many types of reported fibril polymorphism, including different twist patterns. Twist-based polymorphs display unique mechanical properties in vitro, and the relevance of twist polymorphism in amyloid diseases has been suggested. We present transmission electron microscopy images of Aβ42-derived (amyloid β) fibrils, which are associated with Alzheimer’s disease, demonstrating the presence of twist variability even within a single long fibril. To better understand the molecular underpinnings of twist polymorphism, we present a structural and thermodynamics analysis of molecular dynamics simulations of the twisting of β-sheet protofilaments of a well-characterized cross-β model: the GNNQQNY peptide from the yeast prion Sup35. The results show that a protofilament model of GNNQQNY is able to adopt twist angles from −11° on the left-hand side to +8...