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 correspondin