Ahead of the membrane curve: in silico insights into amyloid- β aggregation

Membrane surfaces can accelerate amyloid β (A β ) aggregation, yet the role of mem-brane curvature in this process remains poorly understood. Here, we used multi-million atom all-atom molecular dynamics simulations to compare the adsorption, conforma-tional dynamics, and oligomerization of four A β 42 peptides at a planar neuronal mem-brane and a highly curved lipid vesicle. For both systems, all peptides adsorbed within the first 2 µ s, but their subsequent behavior differed substantially. The curved mem-brane exhibited a larger area per lipid and more extensive hydrophobic packing de-fects, allowing A β 42 to penetrate more deeply and form strong contacts with lipid tails through its central hydrophobic core and C-terminal region. These interactions disrupted a solution-formed dimer and limited peptide-peptide association during the simulated interval. Additionally, vesicle-bound peptides adopted more extended con-formations with increased β -structure and β -hairpin formation compared with peptides at the planar membrane. A β 42 adsorption was also corelated to lipid reorganization in the vesicle. In contrast, the planar membrane supported weaker adsorption and stable dimer-to-trimer growth but showed little large-scale lipid segregation. These findings reveal that curvature reshapes the early A β 42 aggregation landscape by strengthening peptide-lipid interactions, altering aggregation-prone conformations, and reorganizing membrane domains. Membrane geometry should therefore be considered alongside lipid composition in mechanistic models of A β 42 oligomerization and membrane-associated toxicity.