Molecular
Simulation of the Concentration-Dependent
Interaction of Hydrophobic Drugs with Model Cellular Membranes
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Abstract
We report here the interactions between
a hydrophobic drug and
a model cellular membrane at the molecular level using all-atom molecular
dynamics simulations of paclitaxel, a hydrophobic cancer drug. The
calculated free energy of a single drug across the bilayer interface
displays a minimum in the outer hydrophobic zone of the membrane.
The transfer free energy shows excellent agreement with reported experimental
data. In two sets of long-time simulations of high concentrations
of drug in the membrane (12 and 11 mol %), the drugs display substantial
clustering and rotation with significant directional preference in
their diffusion. The main taxane ring partitions in the outer hydrophobic
zone, while the three phenyl rings prefer to be closer to the hydrophobic
core of the membrane. The clustering of the drug molecules, order
parameters of the lipid tails, and water penetration suggest that
the fluidity and permeability of the membrane are affected by the
concentration of drugs that it contains. Furthermore, at the high-concentration
limit, the free energy minimum shifts closer to the hydrophobic core
and the central barrier to cross the membrane decreases. Moreover,
the transfer free energy change substantially increases, suggesting
that increasing concentration facilitates drug partitioning into the
membrane