Molecular Dynamics Simulation Studies of Polycation-DNA Binding for Gene Delivery

Gene therapy is the deliberate introduction of therapeutic DNA into the genome of target cells, a process called transfection. Viral delivery agents, while effective at transfection, can elicit dangerous immunogenic responses. Non-viral gene delivery agents, on the other hand, are not as effective at transfection as viral vectors, but have the advantage of being non-immunogenic. This has lead to increased interest in design of non-viral vectors to improve their transfection efficiencies. Polycations have emerged as promising non-viral delivery agents due to their propensity to bind the polyanionic DNA backbone, neutralizing the charge of the polymer-DNA complex and facilitating endocytosis. Past work has shown that certain polycations such as poly-ethyleneimine (PEI), the current benchmark, are much more effective transfection agents than others such as linear poly-L-lysine[1] and that branched poly-lysines are more effective than linear poly-lysines [2]. Combinatorial approaches have generated a huge number of polycations with differing efficacies [3], but structure-function relationships for these transfection agents are not yet apparent. In this poster we will present molecular simulations that reveal the atomistic interactions in polycation-DNA complexes and elucidate the thermodynamics behind why some polycations are better transfection agents than others.

References: [1] Thomas, M. and Klibanov, A. M. “Non-viral gene therapy: polycation-mediated DNA delivery.” Appl. Microbiol. Biotechnol. 62, 27-34, 2003. [2] Breitenkamp, R. B. and Emrick, T. “Pentalysine-Grafted ROMP Polymers for DNA Complexation and Delivery.” Biomacromolecules 9, 2495-2500, 2008. [3] Barua, S., Joshi, A., Banerjee, A., Matthews, D., Sharfstein, S. T., Cramer, S. M., Kane, R. S., and Rege, K. “Parallel Synthesis and Screening of Polymers for Nonviral Gene Delivery.” Mol. Pharmaceutics 6 (1), 86-97, 2009.