The energy landscape of Aβ42: a funnel to disorder for the monomer becomes a folding funnel for self-assembly

Abstract

The aggregation of amyloid-β (Aβ) peptides, particularly Aβ_1–42, plays a key role in Alzheimer's disease pathogenesis. In this study, we investigate how dimerisation transforms the free energy surface (FES) of the Aβ_1–42 monomer when it interacts with another Aβ_1–42 peptide. We find that the monomer FES is a structurally inverted funnel with a disordered state at the global minimum. However, in the presence of a second Aβ_1–42 peptide, the landscape becomes a folding funnel, leading to a β-hairpin state. Using first passage time analysis, we analyse the pathway for the transition from disordered to the β-hairpin state, which highlights the initial formation of a D23–K28 salt bridge as the driving force, together with hydrophobic contacts.