Atomistic simulation of blood-brain barrier permeability of propolis-derived natural compounds

The ability of small molecules to cross the blood-brain barrier (BBB) remains a major bottleneck in neurotherapeutic development. While experimental assays and machine learning approaches provide approximate permeability estimates, they lack atomistic insight into the underlying transport mechanisms. Here, we employ all-atom molecular dynamics simulations of a compositionally realistic BBB lipid bilayer to characterize the passive permeation of two bioactive propolis-derived compounds, Caffeic Acid Phenethyl Ester (CAPE) and Artepillin-C (ARC). Using steered molecular dynamics and umbrella sampling, we computed free energy profiles, diffusion coefficients, and permeability metrics across the membrane. CAPE shows an interfacial free-energy well (mean PMF ≈ -4.6 kcal mol-1 at d ≈ 0.8 nm) and favorable passive permeability (logPeff = +0.68). In contrast, ARC exhibits a substantial energetic barrier within the membrane core and strongly unfavorable permeability (logPeff = -6.76). The heterogeneous lipid model reproduces experimentally consistent membrane properties and reveals how lipid composition modulates transport energetics. These findings provide mechanistic insight into BBB permeability and demonstrate the utility of atomistic simulations for guiding the design of neuroactive therapeutics.