Modeling β-sheet breaker peptides across multiple resolutions: from neurological targets to liposomal membranes

atomistic and coarse-grained simulations within PEGylated phosphatidylcholine bilayers at varying cholesterol concentrations to assess peptide-lipid interactions and encapsulation potential. Our results indicate that certain peptides may target multiple misfolded proteins, supporting their potential for cross-disease repurposing. Among the candidates, KR peptides exhibited the highest binding free energy toward both targets, while RR peptides demonstrated robust binding with comparable affinity. Multiscale simulations revealed that RR peptides predominantly localize within PEG corona regions and interact with lipid phosphate headgroups, suggesting preferential surface adsorption on pre-formed liposomal fragments. Peptide insertion was more pronounced in unsaturated membranes, whereas cholesterol-rich, saturated membranes hindered permeation and bilayer-to-vesicle transition. Overall, this study provides the first molecular-level insight into the potential of experimentally validated peptides against different neurodegenerative targets and presents a lipid-based delivery strategy to enhance their bioavailability by elucidating the underlying molecular interactions.