Abstract

Self-assembly of the 40/42 amino acid Aβ peptide is a key player in Alzheimers disease. Aβ40 is the most prevalent species, while Aβ42 is the most toxic. It has been suggested that the amino acids 21-30 could nucleate the folding of Aβ monomer and a bent in this region could be the rate-limiting step in Aβ fibril formation. In this study, we review our current understanding of the computer-predicted conformations of amino acids 23-28 in the monomer of Aβ(21-30) and the monomers Aβ40 and Aβ42. On the basis of new simulations on dimers of full-length Aβ, we propose that the ratelimiting step involves the formation of a multimeric β-sheet spanning the central hydrophobic core (residues 17-21).

Keywords: Protein aggregation, simulations, Amyloid-beta, Alzheimer, coarse-grained model, structures, thermodynamics, monomer and dimer