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. Using atomistic and coarse-grained molecular dynamics simulations of DNA and lysine based polycations with and without peptides of nuclear localization sequence (PKKKRKV), we connect the thermodynamics of polycation-DNA binding to experimentally observed transfection efficiency of these polycations. In particular, our computational studies provide enthalpic and entropic contributions to DNA binding free energy and the structure of polycation-DNA complexes as a function of polycation chemistry and architecture.

Thermodynamics guided design of polycations as vectors for DNA delivery

245th National Meeting (2013)

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