Interpeptide interactions induce helix to strand structural transition in Aβ peptides

Replica exchange molecular dynamics and all-atom implicit solvent model are used to compute the structural propensities in A beta monomers, dimers, and A beta peptides bound to the edge of amyloid fibril. These systems represent, on an approximate level, different stages in A beta aggregation. A beta monomers are shown to form helical structure in the N-terminal (residues 13 to 21). Interpeptide interactions in A beta dimers and, especially, in the peptides bound to the fibril induce a dramatic shift in the secondary structure, from helical states toward beta-strand conformations. The sequence region 10-23 in A beta peptide is found to form most of interpeptide interactions upon aggregation. Simulation results are tested by comparing the chemical shifts in A beta monomers computed from simulations and obtained experimentally. Possible implications of our simulations for designing aggregation-resistant variants of A beta are discussed.