Permeation of cisplatin through the membranes of normal and cancer cells: a molecular dynamics study

Abstract

In this work, realistic models of membranes of normal and cancer cells are developed. A special focus is given to their cholesterol content. It is shown that the loss of lipid asymmetry in the membranes of cancer cells leads to a decrease of their permeability to cisplatin by one order of magnitude in comparison to the membranes of normal cells. The change of cholesterol molar ratio from 0% to 33% also decreases the permeability of the membrane by approximately one order of magnitude. The permeability of pure DOPC membrane is 5-6 orders of magnitude higher than one of the membrane with realistic lipid composition, which makes it as an inadequate model for the studies of drug permeability.

Cisplatin-Membrane Interactions and Their Influence on Platinum Complexes Activity and Toxicity

“…It was observed that cisplatin had higher permeability in DOPC membranes compared to complex models of membrane. Moreover, varying the levels of DOPE and DOPS to mimic cancer cells resulted in decreased diffusion compared to asymmetric normal membranes (Rivel et al, 2018). In addition, a variety of external factors (e.g., pH, concentration of ions) can influence membrane composition and fluidity that might result in a higher or lower uptake of platinum(II) complexes.…”

EnCurv: Simple Technique of Maintaining Global Membrane Curvature in Molecular Dynamics Simulations

“…However, the penalty cannot be eliminated completely because EnCurv requires additional computations on top of usual interatomic interactions in the system. In this respect, our previous dummy walls method − is superior because it only adds few nonbond interatomic interactions with dummy particles, which are highly optimized in MD engines, and thus has almost no impact on performance in comparison to free simulations. However, other drawbacks of the dummy walls setup, such as complicated system preparation, unphysical selective repulsive interactions acting on the hydrophobic core of the membrane, and inability to preserve breathing motions and free transversal diffusion of the lipids, makes EnCurv a method of choice despite its inevitable impact on simulation performance.…”

“…In asymmetric membranes with different lipid contents of monolayers, special attention should be paid to prevention of the lipid mixing in the bicelle caps. − In this study, the composition of both monolayers is the same and the mixing of monolayers is not an issue.…”

“…This strain is undesirable because it prevents one from distinguishing effects of curvature itself from the effects of uncontrollable lateral expansions and compression of individual monolayers. One of the most important advantages of our bicelle setup is the absence of the curvature-induced lateral strain of monolayers. − Indeed, the bicelle caps serve as reservoirs that accumulate excessive lipids from compressed concave monolayer and donate them to the expanded convex monolayer. As a result, both monolayers possess an optimal number of lipids, which changes dynamically with curvature.…”

“…The methods from the second group are based on scaffolding the membrane by means of external virtual walls or dummy particles. We utilized this approach with great success in a number of atomistic and coarse-grained simulations in recent years. − In our method, the membrane was confined between two walls of dummy particles, which interact selectively with the carbon atoms of lipid acyl chains only by means of weak purely repulsive nonbonded interactions. These walls scaffold the membrane effectively and allow maintaining any desirable shape and curvature, while lateral diffusion of the lipids and key membrane properties are not affected.…”