Permeation of cisplatin through the membranes of normal and cancer cells: a molecular dynamics study (original) (raw)
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The asymmetry of plasma membranes and their cholesterol content influence the uptake of cisplatin
Scientific Reports, 2019
The composition of the plasma membrane of malignant cells is thought to influence the cellular uptake of cisplatin and to take part in developing resistance to this widespread anti-cancer drug. In this work we study the permeation of cisplatin through the model membranes of normal and cancer cells using molecular dynamics simulations. A special attention is paid to lipid asymmetry and cholesterol content of the membranes. The loss of lipid asymmetry, which is common for cancer cells, leads to a decrease in their permeability to cisplatin by one order of magnitude in comparison to the membranes of normal cells. The change in the 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 membranes with realistic lipid composition, which makes it as an inadequate model for the studies of drug permeability.
2020
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, i...
Link between Membrane Composition and Permeability to Drugs
Journal of chemical theory and computation, 2018
Prediction of membrane permeability to small molecules represents an important aspect of drug discovery. First-principles calculations of this quantity require an accurate description of both the thermodynamics and kinetics that underlie translocation of the permeant across the lipid bilayer. In this contribution, the membrane permeability to three drugs, or drug-like molecules, namely, 9-anthroic acid (ANA), 2',3'-dideoxyadenosine (DDA), and hydrocortisone (HYL), are estimated in a pure 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) and in a POPC:cholesterol (2:1) mixture. On the basis of independent 2-5-μs free-energy calculations combined with a time-fractional Smoluchowski determination of the diffusivity, the estimated membrane permeabilities to these chemically diverse permeants fall within an order of magnitude from the experimental values obtained in egg-lecithin bilayers, with the exception of HYL in pure POPC. This exception is particularly interesting because the ...
The Journal of Physical Chemistry B, 2012
Predicting the permeability coefficient (P) of drugs permeating through the cell membrane is of paramount importance in drug discovery. We here propose an approach for calculating P based on bias-exchange metadynamics. The approach allows constructing from atomistic simulations a model of permeation taking explicitly into account not only the "trivial" reaction coordinate, the position of the drug along the direction normal to the lipid membrane plane, but also other degrees of freedom, for example, the torsional angles of the permeating molecule, or variables describing its solvation/ desolvation. This allows deriving an accurate picture of the permeation process, and constructing a detailed molecular model of the transition state, making a rational control of permeation properties possible. We benchmarked this approach on the permeation of ethanol molecules through a POPC membrane, showing that the value of P calculated with our model agrees with the one calculated by a long unbiased molecular dynamics of the same system.
Experimental Cell Research, 2004
The mechanism of resistance of cancer cells to the anticancer drug cisplatin is not fully understood. Using cisplatin-sensitive KB-3-1 andresistant KCP-20 cells, we found that the resistant cells have higher membrane potential, as determined by membrane potential sensing oxonol dye. Electron spin resonance and fluorescence polarization studies revealed that the resistant cells have more ''fluid'' plasma membranes than the sensitive cells. Because of this observed difference in membrane ''fluidity,'' we attempted modification of the plasma membrane fluidity by the incorporation of heptadecanoic acid into KB-3-1 and KCP-20 cell membranes. We found that such treatment resulted in increased heptadecanoic acid content and increased fluidity in the plasma membranes of both cell types, and also resulted in increased cisplatin resistance in the KCP-20 cells. This finding is in accord with our results, which showed that the cisplatin-resistant KCP-20 cells have more fluid membranes than the cisplatin-sensitive KB-3-1 cells. It remains to be determined whether the observed differences in biophysical status and/or fatty acid composition alone, or the secondary effect of these differences on the structure or function of some transmembrane protein(s), is the reason for increased cisplatin resistance. D
Life
We conduct molecular dynamics simulations of model heterogeneous membranes and their interactions with a 24-amino acid peptide—NAF-144–67. NAF-144–67 is an anticancer peptide that selectively permeates and kills malignant cells; it does not permeate normal cells. We examine three membranes with different binary mixtures of lipids, DOPC–DOPA, DOPC–DOPS, and DOPC–DOPE, with a single peptide embedded in each as models for the diversity of biological membranes. We illustrate that the peptide organization in the membrane depends on the types of nearby phospholipids and is influenced by the charge and size of the head groups. The present study sheds light on early events of permeation and the mechanisms by which an amphiphilic peptide crosses from an aqueous solution to a hydrophobic membrane. Understanding the translocation mechanism is likely to help the design of new permeants.
Pleiotropic resistance (or multidrug resistance, or MDR) to anticancer drugs in malignant diseases takes place either primarily or secondarily in the treatment of cancer. The first report suggesting that MDR could be the result of active drug extrusion was published in 1973 by Dano [1]. A few years later, P-glycoprotein (Pgp) was identified by Juliano and Ling as a membrane protein that actively extrudes membrane embedded drugs. Biochemistry is a "science of contacts" between at least two biochemical elements (e.g. a drug and a transporter). These elements have to interact in order for a reaction to occur (e.g. drug extrusion). Taking into account that drugs do not necessarily incorporate into the membrane in the vicinity of a drug transporter, these transporters have been thought to exhibit a "vacuum cleaner" like-activity on membrane embedded drugs. Accordingly, understanding this activity is essential; as the movement of membrane embedded drugs, or otherwise, movement of the transporters must occur if extrusion is to take place. These activities should be considered as targets for anticancer drugs. Drug movement occurs by lateral diffusion (Brownian movement) in the membrane and the physical conditions required for drug extrusion by membrane transporters is known as the "2D random walk" theory. A deeper understanding is now possible, because there is enough literature enabling understanding of: (a) why the membrane is central to Pgp-* Corresponding author: Email: Cyril.rauch@nottingham.ac.uk, Tel: 0044 (0)115 9516451, Fax: 0044 (0)1115 95 16 440.
Membrane permeability of small molecules from unbiased molecular dynamics simulations
The Journal of Chemical Physics, 2020
Permeation of many small molecules through lipid bilayers can be directly observed in molecular dynamics simulations on the nano- and microsecond timescale. While unbiased simulations provide an unobstructed view of the permeation process, their feasibility for computing permeability coefficients depends on various factors that differ for each permeant. The present work studies three small molecules for which unbiased simulations of permeation are feasible within less than a microsecond, one hydrophobic (oxygen), one hydrophilic (water), and one amphiphilic (ethanol). Permeabilities are computed using two approaches: counting methods and a maximum-likelihood estimation for the inhomogeneous solubility diffusion (ISD) model. Counting methods yield nearly model-free estimates of the permeability for all three permeants. While the ISD-based approach is reasonable for oxygen, it lacks precision for water due to insufficient sampling and results in misleading estimates for ethanol due to...
The journal of physical chemistry. B, 2017
Membrane permeability is a key property to consider during the drug design process, and particularly vital when dealing with small molecules that have intracellular targets as their efficacy highly depends on their ability to cross the membrane. In this work, we describe the use of umbrella sampling Molecular Dynamics (MD) computational modeling to comprehensively assess the passive permeability profile of a range of compounds through a lipid bilayer. The model was initially calibrated through in vitro validation studies employing a Parallel Artificial Membrane Permeability Assay (PAMPA). The model was subsequently evaluated for its quantitative prediction of permeability profiles for a series of custom synthesized and closely related compounds. The results exhibited substantially improved agreement with the PAMPA data, relative to alternative existing methods. Our work introduces a computational model that underwent progressive molding and fine-tuning as a result of its synergistic...