The promise shown by polyethylenimine (PEI) as a non-viral gene therapy vector has been linked with its pH-responsive behavior. As less than half of the amines in PEI are protonated at typical physiological pH, PEI becomes increasingly protonated in acidic environments encountered during the gene delivery process, potentially altering interactions in PEI-nucleic acid complexes and facilitating endosomal release. Despite its importance, the relationship between pH-responsiveness properties of PEI and high transfection efficiencies of PEI-based vectors is not well understood. Here, we use atomistic molecular dynamics simulations to examine how linear PEI depends on protonation to provide a microscopic picture of structural changes in PEI during gene delivery. In general, as PEI transitions from being uncharged to fully protonated, it changes from a compact configuration containing many intrachain hydrophobic interactions to an extended structure. However, the specific behavior underlying this expansion depends on whether the chain is a weak or strong polyelectrolyte, a transition that occurs at a protonation level of ~40%. In the weak polyelectrolyte regime, chain expansion is associated with disruption of most hydrophobic interactions, but, chain stiffness, quantified by the persistence length, is relatively constant. In the strong polyelectrolyte regime, increasing protonation is associated with increasing stiffness and a change in the torsional angle defined by N-C-C-N atoms along the chain backbone. Furthermore, the ionic strength had a stronger effect on the chain size within the strong regime.

Effects of protonation and salt concentration on the structure of polylethylenimine (PEI) in water

2019 Spring National Meeting

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