Simulation Study on the Properties of Cationic Lipid Bilayers and Vesicles

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We are using molecular dynamics simulations to investigate the properties of ionizable cationic lipids forming bilayers and vesicles. This is important for rational design of lipid nanoparticle for delivery of nucleic acids (DNA, RNA). The process of transfection includes encapsulation of anionic biomolecules, binding of the nanoparticle to the membrane surface, endocytosis and release of the nucleic acids from the endosome. For ionizable cationic lipids the steps of this process are pH-dependent. In the acidic environment of the endosome, the charge density of the nanoparticle increases. Membrane disruption is believed to occur due to formation of the ion pairs between cationic lipids in the nanoparticle and anionic lipids in the endosome [Semple et al., Nature Biotech, 2010]. Due to favorable interactions between the headgroups, lipids in the ion pairs become cone-shaped and prone to form non-lamellar phases, such as the inverted hexagonal phase. We simulate cationic and anionic lipid mixtures in bilayers and vesicles and study the mechanism of membrane breakdown upon change of pH/charge density and variation in headgroup size.