(700g) Structural Effects and Translocation of Doxorubicin in a DPPC/Chol Bilayer: The Role of Cholesterol

We use molecular dynamics to help us understand interactions between the anti-cancer drug doxorubicin (DOX) and a model membrane. Using constraint-biased dynamics, we find a potential of mean force (PMF) to characterize the translocation of DOX across a bilayer composed of dipalmitoylphosphatidylcholine (DPPC) and cholesterol (Chol). The PMF gives us an estimate of the energy barrier necessary for DOX to cross the membrane. We find barriers of 24 kT for 0%, 25 kT for 15% and 31 kT for 30% Chol. Our simulations agree with experimental observations regarding increased resistance with increasing Chol content, and show good correlation based on activation energies from Arrhenius plots. A combination of steric hindrance due to tight packing caused by cholesterol as well as DPPC chain disorder determines energy barrier. Steric hindrance increases with cholesterol, however chain order decreases from 0% to 15% Chol, resulting in cancellation of the two contributions and the small 1 kT rise in energy barrier. Both contributions increase from 15% to 30% Chol, resulting in the large increase of 6 kT. We observe a profound impact of DOX on the structure of the bilayer. DPPC head groups are attracted into the bilayer by active sites on the drug, thereby curving the membrane, decreasing its thickness, and allowing water penetration. Water transport is facilitated by the polar sites on the drug.