Probing the Effects of Lipid Substitution on Polycation Mediated DNA Aggregation: A Molecular Dynamics Simulations Study

Understanding the molecular mechanism of DNA aggregation and condensation is of importance to DNA packaging in cells, and applications of gene delivery therapy. Modifying polycations such as polyethylenimine with lipid substitution was found to improve the performance of polycationic gene carriers. However, the role of the lipid substitution in DNA binding and aggregation is not clear and remains to be probed at the molecular level. In this work, we elucidated the role of lipid substitution through a series of all-atom molecular dynamics simulations on DNA aggregation mediated by lipid modified polyethylenimine (lmPEI). We found that the lipids associate significantly with one another, which links the lmPEIs and serves as a mechanism of aggregating the DNAs and stabilizing the formed polyplex. In addition, some lipid tails on the lmPEIs stay at the periphery of the lmPEI/DNA polyplex and may provide a mechanism for hydrophobic interactions. The enhanced stability and hydrophobicity might contribute to better cellular uptake of the polyplexes.