Molecular dynamics insights into the interactions of a potential neurotherapeutic peptide with model liposomes

Peptide molecules capable of disrupting toxic protein aggregates implicated in neurodegenerative diseases hold significant therapeutic potential; however, their clinical translation is constrained by rapid proteolysis and poor penetration into brain tissue. Lipid-based nanoparticles provide a promising delivery platform due to their ability to encapsulate diverse therapeutic cargos, reduce toxicity, and offer high biocompatibility. Here, therefore, we investigated the interactions of a cationic inhibitor peptide, KR, originally developed against Alzheimer's disease, with PC/PG lipid bilayers containing varying cholesterol concentrations using both atomistic and coarse-grained molecular dynamics (MD) simulations. Atomistic simulations revealed that the membrane response to KR is concentration-dependent: higher peptide loadings enhance lipid mobility and slightly increase the area per lipid, especially in cholesterol-free membranes, where deeper insertion facilitates local membrane loosening. KR peptides were preferentially associated with lipid headgroups through electrostatic and hydrogen-bond interactions, predominantly mediated by C-terminal Arg residues. Cholesterol reduced membrane permeability and, in coarse-grained simulations, strengthened both van der Waals and electrostatic interactions with PG lipids, resulting in peptides forming roughly three times more contacts with PG than with PC lipids. Across all systems, KR could not traverse the hydrophobic membrane core from bulk solution, yet peptides were efficiently encapsulated when partially embedded within the bilayer interior. Our study constitutes one of the first multiscale MD investigations of a potential neurotherapeutic peptide at the molecular level and provides mechanistic insights for designing liposomal nanocarriers for peptide delivery to the brain.