Enhancing Oligopeptide-215 Skin Lipid Bilayer Diffusivity via Other Anti-Aging Peptides: A Molecular Dynamics Simulation Study

Efficient delivery of bioactive hydrophilic peptides across the stratum corneum (SC) is a major challenge due to the restricted permeation by the highly ordered lipid matrix, particularly for large or polar molecules. Oligopeptide-215 (OP215) is a biomimetic peptide with reported benefits in promoting cellular repair through enhanced proliferation, adhesion, and migration, but its size and polar/charged residues may limit transport through the SC. Here, we used atomistic molecular dynamics (MD) simulations to investigate whether caffeoyl hexapeptide-9 (CH-9), an anti-aging peptide-caffeic acid conjugate with enhanced skin permeation, can improve OP215 diffusivity across an SC lipid bilayer model. Both OP215 and CH-9 adsorbed onto the bilayer surface and partially inserted below the lipid headgroup region, with OP215 insertion mediated primarily by methionine sidechains and CH-9 insertion by the caffeoyl group. In the co-peptide system, CH-9 co-clustered with OP215 and modestly disrupted free fatty acid packing within the SC lipid bilayer. Position-dependent diffusivity calculations further showed that CH-9 increased the effective diffusivity of OP215 across the bilayer interior by approximately 13%, primarily by enhancing local diffusivity just below the bilayer surface. These results suggest that on top of being an effective anti-aging peptide, CH-9 may act as a permeation-enhancing co-peptide by inducing lipid packing disorder, thereby facilitating OP215 diffusion through the SC lipid matrix. This research provides molecular-level insight into the design of multi-peptide systems for improved topical delivery of functional skincare peptides.