BPS2026 – Molecular dynamics study of DNA membrane penetration via lipoplexes and hydrophobic modification of DNA

DNA forms stable double-helical structures through complementary base pairing. This property has been extensively exploited in DNA nanotechnology to design nanoscale assemblies. Artificial DNA channels created by this method hold promise for applications in diverse fields such as water filtration and drug delivery systems. However, DNA is a negatively charged and highly hydrophilic molecule. As a result, it exhibits poor compatibility with the hydrophobic environment of lipid membranes, which limits its ability to stably associate with or permeate the bilayer. Previous studies have shown that modifying hydrophobic groups into DNA channels improves retention in lipid bilayers, but insertion efficiency into membranes remains low. Thus, developing an effective insertion process is a critical challenge. Meanwhile, it has been reported that the membrane fusion process of DNA-lipid complexes (lipoplexes) induce local membrane rearrangements and transient pore formation. These phenomena may serve as potential pathways for facilitating DNA membrane penetration. Therefore, in this study, we investigated the effects of lipoplexes and hydrophobic modifications on DNA membrane penetration using coarse-grained molecular dynamics simulations. To evaluate the influence of lipoplexes, a model consisting of a single DNA double helix was used as the basic structure, and cationic DOTAP and neutral DOPE were used as the constituent lipids. To examine the effects of hydrophobic modifications on DNA, ethyl and cholesterol groups were introduced as the functional groups to be modified. As a result, cholesterol modifications were found to allow DNA to remain more stably between lipid bilayers during lipoplex-mediated fusion, which could potentially facilitate membrane penetration. In the presentation, we will also discuss particle distributions surrounding DNA and cholesterol to further elucidate the mechanism of membrane penetration.