The Permeation Mechanism of Cisplatin Through a Dioleoylphosphocholine Bilayer**

Abstract

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 anticancer 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 into the polar region of the lipid membrane is controlled, in a first moment, by long-range electrostatic interactions with the choline groups and, in a second step, by long-range electrostatic and hydrogen bond interactions with the phosphate groups. The second half of the permeation pathway, in which cisplatin diffuses through the nonpolar region of the bilayer, is characterized by the drop of the interactions with the polar heads and the rise of attractive interactions with the non-polar tails, which are dominated by van der Waals contributions.

On the Permeation of Polychlorinated Dibenzodioxins and Dibenzofurans through Lipid Membranes: Classical MD and Hybrid QM/MM-EDA Analysis

“…Due to the biological relevance of phosphatidylcholine lipids, DOPC and DPPC membranes are widely chosen as models in experimental and computational investigations. DOPC was chosen as a lipid unit by our group in previous studies of membrane permeability with very satisfactory results in comparison with the available experimental data [ 21 , 23 ]. The membrane was built with the help of the CHARMM-GUI website [ 24 ].…”

Molecular Dynamics Simulation of 2-Benzimidazolyl-Urea with DPPC Lipid Membrane and Comparison with a Copper(II) Complex Derivative

“…Furthermore, membrane fluidity plays a major role in the mechanism of passive diffusion. To function properly, cell membranes must retain fluidity to permit molecular transport into or out of the cell [33]. It was recently suggested that decreased membrane fluidity may affect cisplatin transport into cells while being the main cause of the resistance mechanism and inefficient uptake by target cells [34].…”

Translocation Processes of Pt(II)-Based Drugs through Human Breast Cancer Cell Membrane: In Silico Experiments

“…Ruano et al reported the permeation mechanism of cddp through a membrane model formed by 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) lipids. 18 The potential of mean force (PMF) calculated displayed a barrier of only 0.2 kcal mol −1 to the cddp insertion in the polar heads region of the biomembrane, and an energy barrier of 10.4 kcal mol −1 to reach the hydrophobic center. Nierzwick et al also showed an energy barrier of 12.0 kcal mol −1 for cddp to enter the center of a 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) membrane, thereby indicating a high repulsion to this drug immersed in the lipid tails region.…”

“…The Pt(II)-based drug uptake can be also approached by molecular dynamics (MD) simulations, thereby providing important insights and explanations of the cellular transport at the molecular level. Ruano et al reported the permeation mechanism of cddp through a membrane model formed by 1,2-dioleoyl- sn -glycero-3-phosphocholine (DOPC) lipids . The potential of mean force (PMF) calculated displayed a barrier of only 0.2 kcal mol –1 to the cddp insertion in the polar heads region of the biomembrane, and an energy barrier of 10.4 kcal mol –1 to reach the hydrophobic center.…”