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cisplatin_DOPC_ms.pdf (1.32 MB)
Electrostatic Interactions with Choline and Phosphate Groups Regulate Cisplatin Permeation through a Dioleoylphosphocholine Bilayer
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submitted on 04.09.2020 and posted on 04.09.2020by Lorena Ruano, Gustavo Cárdenas, Juan Jose Nogueira
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.