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.
Highlights
Synthetic polycations have been proposed for many biomedical applications, such as biocides[1] and carriers for the delivery of nucleic acids and proteins.[2]
We focused on changes in the electrostatic potential at the membrane surface and lipid organization in the POPC/POPS
We found that poly([3-(methacryloylamino)propyl]trimethylammonium chloride) (PMAPTAC) binds to the POPC/POPS bilayer due to electrostatic interactions and adopts more compact conformations; the polymer−membrane interactions depend strongly on the length of the polycation
Summary
Synthetic polycations have been proposed for many biomedical applications, such as biocides[1] and carriers for the delivery of nucleic acids and proteins.[2]. It was shown that polycations can associate with, or penetrate into, a negatively charged lipid bilayer.[8,12] the polycation−anionic liposome interactions depend on many factors, such as the type of polycation (weak or strong polyelectrolyte), the total charge of the macromolecule, the charge density on the lipid membrane (anionic lipid fraction), and salt concentration. Strong polycations containing quaternary ammonium groups associate with anionic membranes mainly due to electrostatic interactions. We used atomistic molecular dynamics (MD) simulations and experimental methods to perform an extensive investigation of interactions between strong polycations with different chain lengths and anionic bilayers. We focused on changes in the electrostatic potential at the membrane surface and lipid organization in the POPC/POPS membrane induced by the polycation adsorption.
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