Beyond Co-Existence: α-Synuclein Sequesters Amyloid-β42 into Distinct Hybrid Assemblies

Abstract

Amyloid-{beta} (A{beta}) deposits often appear in Parkinson's disease and -synuclein (-syn) pathology in Alzheimer's disease. As soluble oligomers contribute importantly to cytotoxicity, their early crosstalk is critical to understand. Using all-atom molecular dynamics, we investigated how the initial oligomeric configuration of A{beta}42 shapes its early association with -syn, simulating -syn with (i) one A{beta}42 monomer, (ii) two separated monomers, and (iii) a pre-formed dimer plus a free monomer, across 15 independent 3 s trajectories. Association patterns depended strongly on the initial configuration. With monomeric or nascent dimeric A{beta}42, -syn frequently contacted the metal-binding, central hydrophobic core (CHC), and C-terminal regions, and these contacts were temporally coordinated, most reproducibly the -syn NAC with the A{beta}42 CHC and polar regions. {beta}-hairpin sampling was reduced specifically when -syn engaged the CHC and C-terminus, an interface-dependent rather than a general effect that did not track contact duration, and coincided with more expanded conformations. With a pre-formed dimer, -syn associated mainly peripherally, while the dimer's {beta}-structured interface remained comparatively stable. First-order dihedral entropy differed only modestly between the free and associated states, indicating that association redistributed conformational populations without globally reducing local backbone diversity. Overall, -syn's early structural effect on A{beta}42 is configuration-dependent: it engages and perturbs lower-order species while associating only peripherally with the sampled dimer.