Identifying the Template for Oligomer to Fibril Conversion for Amyloid-β (1-42) Oligomers using Hamiltonian Replica Exchange Molecular Dynamics.

The toxicity of amyloid-β (Aβ) oligomers has been known to be higher compared to mature fibrils. Yet the presence of plaques in Alzheimer's disease patients indicates the significance of oligomer to fibril conversion for Aβ aggregates. In this study, we investigate Aβ 13-42 oligomers having two to five peptide chains using extensive all-atom molecular dynamics simulations to identify the on- or off-pathway intermediates in fibril formation pathway. Hamiltonian replica exchange method through solute tempering (REST2) has been employed to explore the different structures attained by these aggregates. Using intra-chain and inter-chain contacts as reaction coordinates, we obtain the free energy surface for the Aβ 13-42 oligomers. Consequently, their stable conformations and structural features have been identified. The found conformations belonging to most probable structures possess both parallel and anti-parallel β-sheets, characteristic of on- and off-pathway intermediates, respectively. Further, we have measured the tendency to form fibril like interactions among the β-sheet forming residues. Our analysis finds that residues 30-36 possess higher tendency to form fibril like contacts among all the residues. While we find stronger interaction among residues 30-36, these amino acids are also found to be more shielded from water compared to others. With previous experimental studies finding these residues to be more crucial for the stability of Aβ42 oligomers, we propose that interactions within this patch could trigger seed formation that leads to conversion of on-pathway oligomers into disease relevant fibrils.