Electrostatic Interactions with Choline and Phosphate Groups Regulate Cisplatin Permeation through a Dioleoylphosphocholine Bilayer

The investigation of the intermolecular interactions between platinum-based anticancer drugs and lipid bilayers is of special relevance to unveil the mechanisms involved in different steps of the mode of action of these drugs. We have simulated the permeation of cisplatin through a model membrane composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine lipids by means of umbrella sampling classical molecular dynamics simulations. The initial physisorption of cisplatin in the polar region of the membrane is controlled, in a first moment, by long-range electrostatic interactions with the choline groups, which trap the drug in a shallow free-energy minimum. Then, cisplatin is driven to a deeper free-energy minimum by long-range electrostatic interactions with the phosphate groups. From this minimum to the middle of the bilayer the electrostatic repulsion between cisplatin and the choline groups partially cancels out the electrostatic attraction between cisplatin and the phosphate groups, inducing a general drop of the total interaction with the polar heads. In addition, the attractive interactions with the non-polar tails, which are dominated by van der Waals contributions, gain significance. The large energy barrier found when going from the global minimum to the middle of the membrane indicates that the non-electrostatic interactions between the drug and the non-polar tails are badly reproduced by the fixed point-charge force field used here, and that the introduction of polarization effects are likely necessary.