Effects of Membrane-Curvature on Amyloid-Beta Aggregation

Membrane-assisted misfolding and aberrant self-assembly of amyloid beta peptides has been associated with pathogenesis of Alzheimer's disease. While several reports have suggested that an increased membrane curvature can support faster peptide aggregation, a mechanistic explanation of this relationship is missing. In this work, we have explored the effects of membrane curvature on Aβ 16–22 aggregation, using physics-based coarse-grained molecular simulations of model membranes composed of phosphatidylcholine lipids. Our simulations agree with experimental observation of a positive correlation between increased peptide aggregation and membrane curvature. The initial competition between peptide-peptide and peptide-membrane interactions results in three regimes of peptide aggregation behavior, with low curvatures promoting peptides aggregation in solution and high curvatures on membranes. In addition, the membranes with high curvature have higher defects in lipid packing that can engage peptide’s hydrophobic groups and initiate an ordered aggregation into beta-sheet rich structures. Higher curvatures can also promote faster rearrangement of lipid molecules to increase local solvent accessible hydrophobic surface area, that is necessary for membrane associated peptide assemblies.