(178d) Molecular Simulation Studies Relating Polycation Architecture to the Structure and Thermodynamics of Polycation-DNA Complexes

Gene therapy depends on successful transfection of therapeutic DNA by a vector into target cells. Viral vectors, while effective, can elicit harmful immunogenic responses, so ongoing research is focused on non-viral transfection agents. Polycations are a promising class of non-viral vectors due to their ability to bind to the polyanionic DNA backbone, neutralizing the charge of the polycation-DNA complex and facilitating internalization of the genetic material. Combinatorial approaches have generated many polycations with differing efficacies, but structure-activity relationships are elusive. Recent work by Emrick and coworkers [1] has shown that reconfiguring linear polylysine, which is an ineffective vector, into a graftedarchitecture yields much higher transfection efficiency. Using both atomistic and coarse-grained molecular dynamics simulations of these unique polycations, we reveal molecular-level interactions in polycation-DNA binding, thus complementing experimental data with otherwise inaccessible details such as binding free energy, local charge neutralization, and the structure of polycation-DNA complexes [2].

[1] S.S. Parelkar, D. Chan-Seng, and T. Emrick. "Reconfiguring polylysine architectures for controlling polyplex binding and non-viral transfection." Biomaterials.32 (9) pp. 2432-2444 (2011).

[2] R. M. Elder, T. Emrick, and A. Jayaraman. "Understanding the effect of polylysine architecture on DNA binding using molecular dynamics simulations." Biomacromolecules. 12 (11), pp. 3870-3879 (2011).