Loading Capsaicin onto Lipid Bilayers: A Molecular Dynamics Study

Capsaicin is a natural bioactive compound found in chili peppers, with promising potential in various pharmacological applications, including analgesic, antipruritic, anti-inflammatory, anticancer, and antioxidant effects. Its clinical use, however, remains limited due to poor bioavailability, low aqueous solubility, and limited stability. To address these challenges, loading capsaicin in a small liposome bilayer has been proposed to enhance its transport across biological membranes. In this work, we perform molecular dynamics (MD) simulations to study the behavior of capsaicin in lipid bilayers. Two lipid types, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1,2-dipalmitoyl-rac-glycero-3-phosphocholine (DPPC), are used to investigate the effects of unsaturation in the lipid tails. Simulations were conducted under two initial conditions: (1) capsaicin molecules placed in the aqueous phase to study permeation behavior and (2) capsaicin preinserted into the bilayer to assess its equilibrium positioning and to study its behavior in the membrane environment. Our results show that capsaicin tends to aggregate in water with only small aggregates capable of passive permeation into the membrane. The POPC bilayer exhibits a greater capsaicin uptake than the DPPC bilayer, which is attributed to its larger area per lipid. Mass-density profiles indicate the preferred localization of capsaicin within the bilayers, which is consistent with the minimum free energy observed in the potential of mean force (PMF) profiles for translocated molecules into the bilayer. Notably, capsaicin does not significantly change the bilayer thickness and area per lipid when the bilayer is in the liquid phase. It decreases the lipid area per lipid, while maintaining a stable area per capsaicin. The estimated area per capsaicin molecule within the bilayer is 0.415 ± 0.010 nm2. Interestingly, when the bilayer was in the gel phase, the ordered lipid was disrupted by the capsaicin. These findings provide valuable insights into the membrane interactions of capsaicin and support the rational design of liposomal delivery systems to enhance its pharmaceutical potential.