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

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 (PIP₂) 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 PIP₂ lipids and drag the PIP₂ clusters to migrate on the monolayer. The polymer/PIP₂ binding is found to be drastically enhanced by increasing the polymer ionization fraction, which causes the PIP₂ lipids to form into larger clusters and reduces the mobility of the polymer/PIP₂ 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 PIP₂ cluster. The desorbed segments of the anchored polymers exhibit a faster mobility on the membrane, whereas the PIP₂ clusters are closely restrained by the limited adhering cationic segments of anchoring polymers. We further demonstrate that the PIP₂ molecules display a hierarchical mobility in the PIP₂ 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/PIP₂ complexes if the tetravalent PIP₂ 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.