Interactions of Cyclic Peptides Ribifolin and Gramicidin S with Montmorillonite Surface by Molecular Modeling

Cyclic peptides are characterized by remarkable structural stability and considerable therapeutic potential, but their clinical application is often limited by enzymatic degradation, especially in oral administration. Recent approaches, including the design of small cyclic peptides and clay-based delivery systems, aim to improve protection, bioavailability, and controlled release. Among these carriers, layered clay minerals, such as montmorillonite (MONT), are particularly attractive. However, the development of peptide–clay formulations remains largely empirical, since the molecular mechanisms governing adsorption, intercalation, stabilization, and release under hydrated and confined conditions are difficult to probe experimentally. Atomistic simulations using the INTERFACE force field are applied as a preformulation screening strategy to anticipate the behavior of the cyclic peptides ribifolin and gramicidin S at MONT interfaces prior to experimental implementation. Neutral and protonated states are examined, including pH-dependent cation-exchange scenarios relevant to the formulation conditions. The methodology is validated against experimental crystal structures, reproducing lattice parameters with deviations below 6% and demonstrating computational reliability. Protonation enhances peptide stabilization in aqueous media. Energetic analyses show that adsorption on external MONT surfaces is favored over interlayer intercalation, which is predominantly endothermic, whereas desorption into water is exothermic and indicates efficient release under physiological conditions. Although the calculated energies are not full thermodynamic values, the trends reveal how peptide–clay affinities can direct formulation experiments and minimize empirical testing. By integrating molecular modeling with pharmaceutical design, this study supports montmorillonite as a rational platform for the future experimental development of cyclic peptide delivery systems.