Aggregation of Aβ(40/42) chains in the presence of cyclic neuropeptides investigated by molecular dynamics simulations

Alzheimer’s disease is associated with the formation of toxic aggregates of amyloid beta (Aβ) peptides. Despite tremendous efforts, our understanding of the molecular mechanisms of aggregation, as well as cofactors that might influence it, remains incomplete. The small cyclic neuropeptide somatostatin-14 (SST(14)) was recently found to be the most selectively enriched protein in human frontal lobe extracts that binds Aβ(42) aggregates. Furthermore, SST(14)’s presence was also found to promote the formation of toxic Aβ(42) oligomers in vitro. In order to elucidate how SST(14) influences the onset of Aβ oligomerization, we performed all-atom molecular dynamics simulations of model mixtures of Aβ(42) or Aβ(40) peptides with SST(14) molecules and analyzed the structure and dynamics of early-stage aggregates. For comparison we also analyzed the aggregation of Aβ(42) in the presence of arginine vasopressin (AVP), a different cyclic neuropeptide. We observed the formation of self-assembled aggregates containing the Aβ chains and small cyclic peptides in all mixtures of Aβ(42)–SST(14), Aβ(42)–AVP, and Aβ(40)–SST(14). The Aβ(42)–SST(14) mixtures were found to develop compact, dynamically stable, but small aggregates with the highest exposure of hydrophobic residues to the solvent. Differences in the morphology and dynamics of aggregates that comprise SST(14) or AVP appear to reflect distinct (1) regions of the Aβ chains they interact with; (2) propensities to engage in hydrogen bonds with Aβ peptides; and (3) solvent exposures of hydrophilic and hydrophobic groups. The presence of SST(14) was found to impede aggregation in the Aβ(42)–SST(14) system despite a high hydrophobicity, producing a stronger “sticky surface” effect in the aggregates at the onset of Aβ(42)–SST(14) oligomerization.