Effects of Concentration and Ionization Degree of Anchoring Cationic Polymers on the Lateral Heterogeneity of Anionic Lipid Monolayers

Abstract

We employed coarse-grained Monte Carlo simulations to investigate a system composed of cationic polymers and a phosphatidyl-choline membrane monolayer, doped with univalent anionic phosphatidylserine (PS) and tetravalent anionic phosphatidylinositol 4,5-bisphosphate (PIP) lipid molecules. For this system, we consider the conditions under which multiple cationic polymers can anchor onto the monolayer and explore how the concentration and ionization degree of the polymers affect the lateral rearrangement and fluidity of the negatively charged lipids. Our work shows that the anchoring cationic polymers predominantly bind the tetravalent anionic PIP lipids and drag the PIP clusters to migrate on the monolayer. The polymer/PIP binding is found to be drastically enhanced by increasing the polymer ionization fraction, which causes the PIP lipids to form into larger clusters and reduces the mobility of the polymer/PIP complexes. As expected, stronger competition effects between anchoring polymers occur at higher polymer concentrations, for which each anchoring polymer partially dissociates from the monolayer and hence sequesters a smaller PIP cluster. The desorbed segments of the anchored polymers exhibit a faster mobility on the membrane, whereas the PIP clusters are closely restrained by the limited adhering cationic segments of anchoring polymers. We further demonstrate that the PIP molecules display a hierarchical mobility in the PIP clusters, which is regulated by the synergistic effect between the cationic segments of the polymers. The PS lipids sequester in the vicinity of the polymer/PIP complexes if the tetravalent PIP lipids cannot sufficiently neutralize the cationic polymers. Finally, we illustrate that the increase in the ionic concentration of the solution weakens the lateral clustering and the mobility heterogeneity of the charged lipids. Our work thus provides a better understanding of the fundamental biophysical mechanism of the concentration gradients and the hierarchical mobility of the anionic lipids in the membrane caused by the cationic polymer anchoring on length and time scales that are generally inaccessible by atomistic models. It also offers insight into the development and design of novel biological applications on the basis of the modulation of signaling lipids.

Heterogeneity in Lateral Distribution of Polycations at the Surface of Lipid Membrane: From the Experimental Data to the Theoretical Model

“…This charge density was found independent of the ionic strength of the solution for each type of the polymers, while the surface potential was altered in full accordance with the prediction of the Gouy–Chapman model. A similar conclusion was drawn in a series of works by Duan et al [ 86 , 87 ]. The authors applied the Monte Carlo method for the analysis of the efficiency of linear model polycation adsorption on the surface of membranes with different content of anionic lipids.…”

“…Lateral diffusion and mobility of charged lipids in these membranes decrease in the presence of a polycation layer, which facilitates their clustering, while the mobility of zwitterionic lipids remains unchanged. Lipid clustering was also observed in the Monte Carlo simulations of a model polymer on the membrane from the mixture of phosphatidylinositol 4,5-bisphosphate/phosphoserine/phosphocholine (PIP 2 /PS/PC) [ 86 , 115 ]. Numerical simulations show that charged lipid clusters include mainly PIP 2 molecules (4 e per lipid), and their aggregation becomes more prominent with an increase in polycation degree of ionization [ 86 ] or polymerization [ 115 ].…”

“…Lipid clustering was also observed in the Monte Carlo simulations of a model polymer on the membrane from the mixture of phosphatidylinositol 4,5-bisphosphate/phosphoserine/phosphocholine (PIP 2 /PS/PC) [ 86 , 115 ]. Numerical simulations show that charged lipid clusters include mainly PIP 2 molecules (4 e per lipid), and their aggregation becomes more prominent with an increase in polycation degree of ionization [ 86 ] or polymerization [ 115 ]. Single-charged lipids PS aggregate under polycations only upon the shortage of PIP 2 molecules needed for neutralization of the polymer charge.…”

“…Single-charged lipids PS aggregate under polycations only upon the shortage of PIP 2 molecules needed for neutralization of the polymer charge. The efficiency of the clustering of charged lipids decreases with increasing ionic strength of the solution [ 86 , 87 ].…”

Structures of cationic and anionic polyelectrolytes in aqueous solutions: the sign effect

“…1, following the derivation of our prior works and other previous studies. 10,22,24,55–66 The ions and PEs considered in this study are all hydrophilic.…”