Cell membranes are the main and often final barriers in drug delivery. But it is not well known how most hydrophobic drugs such as paclitaxel penetrate through cell membranes. Paclitaxel tends to aggregate both in hydrophilic and hydrophobic environments. Additionally it has been shown to induce stable pores across the membrane. To investigate interactions between paclitaxel and a model cell membrane of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) at a molecular level, we used multiscale molecular dynamics simulations with all-atom and coarse-grained models. The profile of free energy across the bilayer interface calculated by adaptive biasing force method showed a minimum at around outer hydrophobic zone and the free energy change showed good agreement with experimental data. We performed and compared two sets of 300ns-long simulations of POPC membranes with the drugs up to 0.1 mole fraction: one set with randomly inserted drugs and the other with drugs initially inserted at lattice points with a single orientation. The main baccatinic core preferred to position at outer hydrophobic zone, while the three hydrophobic phenyl rings moved closer to the hydrophobic core of the membrane. This was consistent with the rotation and orientation of the drug. The rotations of drugs were clearer in the second set. The clustering of the drug molecules in the membrane, order parameters of lipid tails, and water penetration along with the drug clusters were analyzed over time. Modeling the transport of hydrophobic drugs into the cell through computational investigations will provide molecular-level insights of the drug delivery process.

Multiscale modeling of paclitaxel interacting with cellular membranes

247th National Meeting (2014)

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