BPS2026 – Decoding the self-assembly of membrane-spanning DNA channels using molecular simulations

Creating synthetic biosystems that reproduce the functionality and outperform naturally evolved biological systems is one of the long-lasting challenges in nanotechnology. DNA nanotechnology offers a route to create custom-shaped functional nanostructures with subnanometer precision. Among the myriad DNA based nanostructures, lipid membranes anchored DNA nanopores are particularly interesting due to their promising applications in synthetic biology, such as mimicking membrane remodeling proteins and functioning as artificial enzymes. These hydrophobically modified DNA nanostructures form transmembrane channels, facilitating the permeation of water, ions, and small molecules. However, the self-assembly of the negatively charged DNA barrels in amphiphilic membranes is yet to be fully understood since their inception in 2012. Here, we investigate the spontaneous self-assembly of a duplex DNA in phospholipid membrane using equilibrium and advanced sampling molecular dynamics simulations. We examine the influence of nucleic acids on the kinetics of membrane formation by introducing cholesterol anchored DNA into the lipid environment. Our results suggest that DNA can modulate the assembly pathway, potentially accelerating bilayer organization through non-bonded DNA lipid interactions. To gain mechanistic insights into the self-assembly pathways, we employ metadynamics to explore the free-energy landscape of DNA driven nanopore formation. Our study provides a molecular-level perspective on lipid-DNA interactions and their implications in synthetic membrane engineering and DNA nanotechnology.