(702a) Molecular Simulations of Macromolecular Materials for Non-Viral Gene Delivery

Gene delivery involves successful transfection of therapeutic plasmid DNA by a vector into target cells. Viral vectors, while effective, can elicit immunogenic responses, so ongoing research is focused on non-viral transfection agents. Polycations are a promising route of development due to their propensity to bind the polyanionic DNA backbone, neutralizing the charge of the polymer-DNA complex and facilitating endocytosis. In the past few years, innovative synthesis has lead to many polycations of varying chemistry and architecture exhibiting differing efficacies as gene delivery vectors. Certain polymers such as poly-ethyleneimine (PEI) are much more effective than others such as linear poly-L-lysine (PLL), while certain branched PLL architectures are more effective than linear PLL [1]. Despite this significant progress in synthesis, generalized relationships between polycation structure and DNA binding activity remain elusive.  Using molecular dynamics simulations and free energy calculations we reveal molecular-level interactions in polycation-DNA binding that could explain the improved/reduced efficiency of certain polycations as gene delivery vectors. This talk will focus specifically on how architecture of lysine based polymers – linear versus branched-, and varying graft length and graft spacing in grafted oligo-lysines affects the location of molecular contacts between the polycation and DNA, local charge neutralization, and polycation-DNA binding thermodynamics.

1. Parelkar S. S., Chan-Seng D, Emrick T Reconfiguring polylysine architectures for controlling polyplex binding and non-viral transfection BIOMATERIALS    32   (9)   Pages: 2432-2444   (2011 )