Polycation–Anionic Lipid Membrane Interactions

Abstract

Natural or synthetic polycations are used as biocides or as drug/gene carriers. Understanding the interactions between these macromolecules and cell membranes at the molecular level is therefore of great importance for the design of effective polymer biocides or biocompatible polycation-based delivery systems. Until now, details of the processes at the interface between polycations and biological systems have not been fully recognized. In this study, we consider the effect of strong polycations with quaternary ammonium groups on the properties of anionic lipid membranes that we use as a model system for protein-free cell membranes. For this purpose, we employed experimental measurements and atomic-scale molecular dynamics (MD) simulations. MD simulations reveal that the polycations are strongly hydrated in the aqueous phase and do not lose the water shell after adsorption at the bilayer surface. As a result of strong hydration, the polymer chains reside at the phospholipid headgroup and do not penetrate to the acyl chain region. The polycation adsorption involves the formation of anionic lipid-rich domains, and the density of anionic lipids in these domains depends on the length of the polycation chain. We observed the accumulation of anionic lipids only in the leaflet interacting with the polymer, which leads to the formation of compositionally asymmetric domains. Asymmetric adsorption of the polycation on only one leaflet of the anionic membrane strongly affects the membrane properties in the polycation–membrane contact areas: (i) anionic lipid accumulates in the region near the adsorbed polymer, (ii) acyl chain ordering and lipid packing are reduced, which results in a decrease in the thickness of the bilayer, and (iii) polycation–anionic membrane interactions are strongly influenced by the presence and concentration of salt. Our results provide an atomic-scale description of the interactions of polycations with anionic lipid bilayers and are fully supported by the experimental data. The outcomes are important for understanding the correlation of the structure of polycations with their activity on biomembranes.

Effect of polycation nanostructures on cell membrane permeability and toxicity

“…6A). 37 The zeta potential measurements and calcein release experiments confirmed that PAM effectively adhered to the POPC/DOPA liposomes neutralizing anionic lipids but did not alter membrane permeability. In turn, hydrophobically modified polycations can penetrate the lipid bilayer by incorporating their alkyl groups and cause disorder in the acyl chains of the lipid molecules.…”

PAMAM-Functionalized Cellulose Nanocrystals with Needle-Like Morphology for Effective Cancer Treatment

“…The main reason for the toxicity of the carrier is that the cation can interfere with the structure of the cell membrane, which causes the death of the cell [ 28 ]. The positive charge of cationic compounds is a double-edged sword.…”

Reversal Activity and Toxicity of Heparin-Binding Copolymer after Subcutaneous Administration of Enoxaparin in Mice

“…Polycation–polyanion complexes can cause adverse effects such as inflammation [ 34 , 35 ]. On the other hand, cationic compounds can impair the liver function [ 36 , 37 , 38 ], interact with anionic cell lipid membranes [ 39 , 40 ], impact clot morphology [ 41 , 42 ], lyse erythrocytes [ 43 ], generate cellular [ 44 ] and hematological [ 45 , 46 ] toxicity, and increase LDH levels associated with inflammatory disorders [ 47 ]. Therefore, it is not clear if hepatotoxicity is associated directly with the HBC–ENX complexes or the excess of polycationic HBC.…”