An atomic model for the pleated beta-sheet structure of A beta amyloid protofilaments

Synchrotron x-ray studies on amyloid fibrils have suggested that the stacke d pleated beta-sheets are twisted so that a repeating unit of 24 beta-stran ds 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 beta-sheet of human A beta amyloid protofilament. In the model, A beta monomers of A beta 12-42 stack (four p er layer) to form a helical turn of beta-sheet, Each monomer is in an antip arallel beta-sheet conformation with a turn located at residues 25-28. Resi dues 17-21 and 31-36 form a hydrophobic core along the fibril axis. The hyd rophobic core should play a critical role in initializing A beta aggregatio n and in stabilizing the aggregates. The model was tested using molecular d ynamics simulations in explicit aqueous solution, with the particle mesh Ew ald (PME) method employed to accommodate long-range electrostatic forces. B ased 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 amyl oid fibrils is likely the result of stabilizing packing interactions of the protofilaments, The model also provides a binding mode for Congo red on A beta amyloid fibrils. The model may be useful for the design of A beta aggr egation inhibitors.