Molecular-level insight into the interactions of DNA with phospholipid bilayers: barriers and triggers

Interactions of nuclear acids with cell membranes are at the heart of numerous biomedical and nanotechnological applications of DNA and DNA-based nanodevices. Despite enormous recent development in DNA nanotechnology, very little is known about DNA-membrane interactions at a molecular level. Here we employ biased atomic-scale computer simulations to calculate for the first time the free energy profile for partitioning a DNA molecule into a phospholipid bilayer, a system that is routinely used to mimic the properties of cell membranes. Our findings clearly show that a zwitterionic lipid bilayer represents a repulsive barrier for DNA: the potential of the mean force profile does not develop any local minima upon moving DNA from water into the lipid/water interface. This energetic barrier can be overcome e.g. via adsorption of divalent calcium ions on the surface of a lipid bilayer, which makes the lipid bilayer effectively cationic. Indeed, our biased molecular dynamics simulations confirm that the corresponding free energy profile for partitioning DNA into a lipid bilayer with adsorbed Ca ions is characterized by a deep minimum. Therefore, the bilayer-bound calcium ions can serve as a trigger of the electrostatic attraction between DNA and zwitterionic phospholipids. In addition, we performed a series of unbiased computer simulations for lipid bilayers with absorbed calcium ions and showed that the initial DNA binding is driven by an overall positive charge of the bilayer, while DNA is stabilized on the bilayer surface by Ca ions that laterally diffuse towards DNA to form tight bridges between phosphate groups of DNA and lipids. Overall, our computational findings contribute to a long-standing problem of interactions of charged nano-objects (such as DNA and DNA-base nanostructures) with cell membranes.