A computational study of Anthracyclines interacting with lipid bilayers: Correlation of membrane insertion rates, orientation effects and localisation with cytotoxicity

D Toroz,I R Gould

doi:10.1038/s41598-019-39411-y

Abstract

Anthracyclines interact with DNA and topoisomerase II as well as with cell membranes, and it is these latter interactions that can cause an increase in their cytotoxic activity. In the present study a detailed computational analysis of the initial insertion, orientation and nature of the interaction occurring between Anthracyclines and two different lipid bilayers (unsaturated POPC and saturated DMPC) is explored through molecular dynamics (MD) simulations; four Anthracyclines: Doxorubicin (DOX), Epirubicin (EPI), Idarubicin (IDA) and Daunorubicin (DAU) were examined. The results indicate that the increased cytotoxicity of DOX, in comparison to the other three analogues, is correlated with its ability to diffuse at a faster rate into the bilayers. Additionally, DOX exhibited considerably different orientational behaviour once incorporated into the bilayer and exhibited a higher propensity to interact with the hydrocarbon tails in both lipids indicating a higher probability of transport to the other leaflet of the bilayer.

Highlights

A significant problem in the treatment of cancer patients is the multidrug-resistance (MDR) phenotype which is associated with a decreased intracellular accumulation of the drug that appears to be mediated by the membrane glycoprotein, P-glycoprotein[1]
From Tian et al.[27] the association constant Kin is calculated from the equation where A is the size of the phospholipid surface and Lz is the thickness of the water layer that the analogue diffuses in to the bilayer and is the mean first passage time that each of the analogues reaches the surface of the lipid
The success of membrane insertion observed from this study were in the rank order DOX

Summary

Introduction

A significant problem in the treatment of cancer patients is the multidrug-resistance (MDR) phenotype which is associated with a decreased intracellular accumulation of the drug that appears to be mediated by the membrane glycoprotein, P-glycoprotein[1]. Molecular dynamics simulations are a powerful tool as they can permit a detailed analysis of the contribution of the lipid components as well as the dynamics of the membrane bilayer when interacting with antitumor drugs This manuscript reports the interactions occurring at the atomic level of detail between the four cancer therapeutic Anthracyclines with lipid bilayers and examines their behaviour in respect of their spontaneous membrane insertion, orientation and their location preferences when they are transported into a biological membrane environment. This manuscript reports on three key parameters (a) the initial membrane insertion times of the four analogues i.e. how fast each of the analogues enters the lipid bilayer, (b) the orientational position they prefer to retain in respect of the Z-direction of the lipid bilayer once inserted and (c) their location preferences into the different components of the lipids

Objectives

Methods

Results

Conclusion