Design of Sulfobetaine-Lysine Copolymers for DNA Complexation and Delivery: Molecular Simulations and Experiments

Gene delivery is the process of introducing therapeutic DNA into the body in order to express proteins that help in curing diseases. Cationic polymers (polycations) are a promising class of non-viral DNA delivery agents that show lower immunogenic responses than viral DNA delivery agents. The electrostatic interactions between positively-charged polymers and negatively-charged DNA leads to formation of stable DNA-polycation complexes (polyplexes), which protect the therapeutic DNA from degradation and facilitate safe transfection of the therapeutic DNA. To maximize DNA transfection efficiency, one needs to tune the polyplex structure and surface chemistry, which are a function of the polycation chemistry and architecture, and the resulting polycation-DNA complexation. In this talk, we present our latest computational results describing the effects of incorporating sulfobetaine zwitterions into lysine-based comb polycations on polymer-DNA binding, and the resulting polyplex features. Our coarse-grained molecular simulations  provide molecular-level understanding of how sulfobetaine content in the lysine based polymer impacts polyplex size, shape, surface composition and polymer-DNA binding. The computational results of polymer-DNA binding affinity and surface charge as a function of sulfobetaine content are in agreement with in vitro studies conducted by Emrick and coworkers; this serves as a validation for our coarse-grained simulations.