We utilize various computational methodologies to study menthol's interaction with multiple organic phases, a lipid bilayer, and the human α4β2 nicotinic acetylcholine receptor (nAChR), the most abundant nAChR in the brain. First, force field parameters developed for menthol are validated in alchemical free energy perturbation simulations to calculate solvation free energies of menthol in water, dodecane, and octanol and compare the results against experimental data. Next, umbrella sampling is used to construct the free energy profile of menthol permeation across a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer. The results from a flooding simulation designed to study the water-membrane partitioning of menthol in a POPC lipid bilayer are used to determine the penetration depth and the preferred orientation of menthol in the bilayer. Finally, employing both docking and flooding simulations, menthol is shown to bind to different sites on the human α4β2 nAChR. The most likely binding mode of menthol to a desensitized membrane-embedded α4β2 nAChR is identified to be via a membrane-mediated pathway in which menthol binds to the sites at the lipid-protein interface after partitioning in the membrane. A rare but distinct binding mode in which menthol binds to the extracellular opening of receptor's ion permeation pore is also reported.
ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Surfaces, Coatings and Films
- Materials Chemistry