Effects of Nicotine on the Thermodynamics and Phase Coexistence of Pulmonary Surfactant Model Membranes

Phase separation is essential for membrane function, and alterations in phase coexistence by membrane-interacting molecules, such as nicotine, can impair membrane stability. With the increasing use of e-cigarettes, concerns have arisen about the impact of nicotine on pulmonary surfactants. Here, we used differential scanning calorimetry (DSC), molecular dynamics (MD) simulations, and electron spin resonance (ESR) to examine nicotine's effect on the phase coexistence of two surfactant models: pure DPPC and a DPPC/POPC/POPG mixture. Our DSC analysis revealed that nicotine interacts with both membranes, increasing enthalpy and entropy change during the phase transition. ESR revealed that nicotine affects membrane fluidity and packing of DPPC more effectively than the ternary mixture, especially near the surface. MD simulations showed that neutral nicotine resides in the mid-plane, while protonated nicotine remains near the surface. Nicotine binding to the membranes is dynamic, switching between bound and unbound states. Analysis via ESR/van't Hoff method revealed changes in the thermodynamics of phase coexistence, yielding distinct non-linear behavior. Nicotine altered the temperature dependence of the free energy, modifying the thermodynamic driving forces and the balance of non-covalent lipid interactions. These findings provide new insights into how nicotine influences pulmonary surfactant model membranes, with potential implications for surfactant function.