We report the interactions of a hydrophobic anti-cancer drug paclitaxel in a model cellular membrane at the molecular level using all-atom molecular dynamics simulations. The calculated free energy of a single drug across the bilayer interface shows excellent agreement with reported experimental data. In two sets of long-time simulations of high concentrations of drug in the membrane, the drugs display substantial clustering and rotation with significant directional preference in their diffusion. The main taxane ring prefers to be in the outer hydrophobic zone, while the three phenyl rings partition closer to the hydrophobic core of the membrane. The clustering of the drug molecules, decreased order parameters of the lipid tails, and enhanced penetration of water indicate that the fluidity and permeability of the membrane are affected by the concentration of drugs that it contains. The calculated free energy reveals that the distribution and the transportability of the drug in the membrane are affected by the concentration, which facilitates drug partitioning into the membrane. Our atomistic simulation results give us the base to build and refine coarse-grained models for multiscale simulations to further study the whole process. A better understanding of the interactions between hydrophobic drugs and model membranes at a molecular level will help design more efficient drug delivery systems.

Molecular simulation of concentration-dependent interactions of hydrophobic drugs with cellular membrane

251st National Meeting (2016)

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