Effects of applied surface-tension on membrane-assisted Aß aggregation.

Accumulation of protein-based (Aß) aggregates on cellular membranes with varying structural properties is commonly recognized as the key step in Alzheimer's pathogenesis. But experimental and computational challenges have made this biophysical characterization difficult. In particular, studies connecting biological membrane organization and Aß aggregation are limited. While experiments have suggested that an increased membrane curvature results in faster Aß peptide aggregation in the context of Alzheimer's disease, a mechanistic explanation for this relation is missing. In this work, we are leveraging molecular simulations with a physics-based coarse grained model to address and understand the relationships between curved cellular membranes and aggregation of a model template peptide Aß 16-22. In agreement with experimental results, our simulations also suggest a positive correlation between increased peptide aggregation and membrane curvature. More curved membranes have higher lipid packing defects that engage peptide hydrophobic groups and promote faster diffusion leading to peptide fibrillar structures. In addition, we curated the effects of peptide aggregation on the membrane's structure and organization. Interfacial peptide aggregation results in heterogeneous headgroup-peptide interactions and an induced crowding effect at the lipid headgroup region, leading to a more ordered headgroup region and disordered lipid-tails at the membrane core. This work presents a mechanistic and morphological overview of the relationships between the biomembrane local structure and organization, and Aß peptide aggregation.