Model amyloid peptide B18 monomer and dimer studied by replica exchange molecular dynamics simulations

Peptide misfolding and aggregation are the early steps during the formation of amyloid fibrils. Understanding these processes in detail is crucial for the development of therapeutic strategies against amyloid diseases. Here I present temperature replica exchange molecular dynamics (TREMD) simulations of the model amyloid peptide B18 in the mono- and dimeric states in explicit aqueous solution. Both the monomer and the dimer involve β-sheets consisting of different residues in different registers with comparable statistical weight. The dimer forms intra- as well as intermolecular β-sheets. The average β-sheet content is in agreement with previous estimates from circular dichroism (CD) spectra for monomers and is lower for dimers. The tendency of B18 to form β-sheets likely contributes to its fibrillogenic property. For both the monomer and the dimer, individual peptides form U-shaped or other partially collapsed conformations. Combined with data from electron microscopy, this suggests that for higher aggregates during fibrillization B18 undergoes a transition from U-shaped to outstretched conformations. The tendency of B18 to form U-shaped conformations, intramolecular β-sheets, and intermolecular β-sheets with different register will contribute to the lag phase for fibril formation.