An Atomic Model for the Pleated β-Sheet Structure of A β Amyloid Protofilaments

Abstract

Synchrotron x-ray studies on amyloid fibrils have suggested that the stacked pleated β-sheets are twisted so that a repeating unit of 24 β-strands forms a helical turn around the fibril axis (Sunde et al., 1997. J. Mol. Biol. 273:729–739). Based on this morphological study, we have constructed an atomic model for the twisted pleated β-sheet of human A β amyloid protofilament. In the model, 48 monomers of A β 12–42 stack (four per layer) to form a helical turn of β-sheet. Each monomer is in an antiparallel β-sheet conformation with a turn located at residues 25–28. Residues 17–21 and 31–36 form a hydrophobic core along the fibril axis. The hydrophobic core should play a critical role in initializing A β aggregation and in stabilizing the aggregates. The model was tested using molecular dynamics simulations in explicit aqueous solution, with the particle mesh Ewald (PME) method employed to accommodate long-range electrostatic forces. Based on the molecular dynamics simulations, we hypothesize that an isolated protofilament, if it exists, may not be twisted, as it appears to be when in the fibril environment. The twisted nature of the protofilaments in amyloid fibrils is likely the result of stabilizing packing interactions of the protofilaments. The model also provides a binding mode for Congo red on A β amyloid fibrils. The model may be useful for the design of A β aggregation inhibitors.