Molecular-Level Insight into the Interactions of DNA/Polycation Complexes with Model Cell Membranes

The interactions of DNA/polycation complexes (polyplexes) with cell membranes are crucial for understanding the molecular mechanisms behind polycation-mediated delivery of nucleic acid therapeutics into the target cells. In this study, we employed both biased and unbiased atomic-scale computer simulations to get an insight into such interactions. To this end, we considered complexes of DNA with linear polyethylenimine (PEI) with various polycation contents, ranging from an almost fully neutralized DNA to a highly overcharged polyplex. Our findings clearly show that the free energy gradually increases when a polyplex approaches the surface of a zwitterionic (neutral) phospholipid membrane from bulk water, implying the lack of attractive polyplex/membrane interactions. Remarkably, overcharging of DNA molecules by polycations enhances the repulsion between the polyplex and the zwitterionic lipid membrane. The observed repulsion is most likely driven by the dehydration of a polyplex upon its partitioning into the zwitterionic lipid membrane as well as by the loss of conformational entropy of PEI chains. We also demonstrate that cationic polymer chains are able to protect DNA from the dehydration as well as from contacts with lipid molecules. Interestingly, the absence of local minima in the free energy profiles does not exclude transient weak adsorption of a polyplex on the zwitterionic membrane surface. We show that such spontaneous adsorption can indeed be initiated by the interactions of loose polycation chains of the polyplex with polar head groups of lipids. Overall, our computational findings contribute considerably to the understanding of the initial stages in polycation-mediated DNA transfection. In particular, we demonstrate that a zwitterionic lipid bilayer represents an energetic barrier for polyplexes, so that a proper model of the cell membrane should account for the anionic surface charge of the membrane (e.g., due to the presence of proteoglycans).