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

Abstract

β-Sheet-breaker peptides can destabilize protein aggregates associated with neurological disorders, thereby interfering with fibril formation. Given the pivotal role of misfolded protein oligomers such as amyloid-β and α-synuclein in Alzheimer's and Parkinson's diseases, respectively, strategies that block β-sheet formation or perturb β-sheet-rich interactions are promising therapeutic approaches to mitigate neurotoxicity and slow disease progression. However, cross-applicability of inhibitor peptides between these diseases remains largely unexplored. Moreover, the clinical potential of β-sheet-breaker peptides is often limited by enzymatic degradation and restricted blood–brain barrier permeability, necessitating effective delivery systems. To address these challenges, lipid-based nanocarriers offer versatile platforms for peptide encapsulation and controlled release. Therefore, in this study, we collected 50 experimentally validated β-sheet-breaker peptides and examined their binding to amyloid-β and α-synuclein fibrils using molecular docking and molecular dynamics simulations. The selected peptide was further evaluated via 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.