Cationic lipid membranes condense double-strand DNA through ion bridging.

Abstract

Cationic lipid (CL)-DNA complexes have attracted much attention due to their potential application in somatic gene therapy, such as nonviral transfection vectors. The rational design of efficient synthetic vectors requires a systematic understanding of the underlying mechanisms governing CL-DNA assembly. Experimental studies show that DNA double strands form assemblies in divalent cations when confined between CL lipid systems. The physical mechanism of membrane-induced condensation is not well understood. Herein, we present a computational study of a simplified vector system, quasi-random genomic DNA chains intercalated into DOPC/DOTAP membrane bilayers. Using all-atom molecular dynamics simulations and free energy calculations, we observe attraction between dsDNA pairs when the ionic strength of the solution and mole fraction of DOPC mimic experimental conditions. Strikingly, the same salt conditions favoring condensation in CL lead to repulsion without the lipid. We investigated the role of lipids and confined cations to understand the differences in DNA-DNA interactions. Simulations suggest that the head groups of the lipids in contact with the DNA backbone reduce the DNA charges. The cationic DOTAP and zwitterionic DOPC head groups form direct contact with the DNA backbone. In addition, the DOPC phosphate head groups are glued to the DNA backbone by magnesium cations. The already reduced opposite surface of DNA double strands are brought together with dynamically bridging magnesium cations confined between the two helices. Our study offers physical insight into the mechanism of CL-DNA assembly and may help to facilitate the development of liposome transfer vectors for gene delivery.