Molecular mechanisms of direct and indirect interplay between amyloid β42 oligomer and characteristic lipids

Accumulating evidence suggests that toxicity in patients with Alzheimer's disease originates from the deposition of Aβ42 aggregates on the neuronal cell membrane. However, the molecular mechanism underlying Aβ42 aggregation on the surface of different lipids is poorly understood. In this study, coarse-grained and all-atomic molecular dynamics (MD) simulations were used to characterize the assembly process of two Aβ42 pentameric oligomers and the perturbation “footprints” of three characteristic lipid constitute bilayer membranes: POPC, POPG, and their hybrid PcPg composed of POPG and POPC in a 1:3 ratio. Our results revealed that the Aβ decamer was first formed in the water phase prior to its contact with the lipid surface, indicating that the water phase plays an incubation role in Aβ42 oligomer aggregation. Moreover, the presence of any of the three lipids accelerated the assembly process of the two Aβ42 pentameric. The aggregation rate and aggregate conformation were strictly dependent on lipid charge, oligomer size, and degree of aggregation. In turn, the presence of oligomer impacted the surface of the lipid, generating a clear perturbation “footprint”, regardless of whether the interplay was direct or indirect, revealing for the first time that the indirect interaction is not seamless and can be detected clearly at the molecular level. Indirect interplay stands for the non-contacting interaction interfaced by the water phase, indicating a metastable state with long-range interaction under non-shaking conditions. Our results reveal the crucial role of non-contacting interactions in determining the phase status of zwitterionic membranes.