Investigating Self‐Assembly of Oppositely Charged Cyclic Peptides And Its Application Toward Drug Entrapment

ABSTRACT The self‐assembly of oppositely charged cyclic peptides offers a route to stable nanotubes for molecular encapsulation. We used molecular dynamics (MD) to probe self‐assembly of lysine–aspartic acid and lysine–glutamic acid 24‐residue rings in water, tetrahydrofuran (THF), and hexane. Hydrogen‐bonding, solvent‐accessible surface area, radius of gyration, and pore geometry analyses revealed strong solvent dependence. Water strongly solvated the peptides and weakened inter‐peptide contacts whereas hexane promoted aggregation of the charged peptides. THF produced compact, ordered nanotubes with well‐defined channels, identifying it as the most favorable medium. THF‐stabilized assemblies were then assessed for loading the anticancer drug, 5‐fluorouracil. Multiple molecules were found at the peptide interface and inside the central pore, suggesting effective loading and strong binding. Potentials of mean force calculations showed deep minima (–18 to –20 kcal ), consistent with stable confinement. These results demonstrate that oppositely charged cyclic peptides form robust tubular nanostructures that encapsulate small polar molecules, supporting their use as versatile carriers for drug delivery.