Molecular Dynamics Simulations of DNA/PEI Complexes: Effect of PEI Branching and Protonation State

Abstract

Complexes formed by DNA and polyethylenimine (PEI) are of great research interest because of their application in gene therapy. In this work, we carried out all-atom molecular dynamics simulations to study eight types of DNA/PEI complexes, each of which was formed by one DNA duplex d(CGCGAATTCGCG)(2) and one PEI. We used eight different PEIs with four different degrees of branching and two protonation ratios of amine groups (23% and 46%) in the simulations to investigate how the branching degree and protonation state can affect the binding. We found that 46% protonated PEIs form more stable complexes with DNA, and the binding is achieved mainly through direct interaction between the protonated amine groups on PEI and the electronegative oxygens on the DNA backbone, with some degree of interaction with electronegative groove nitrogens/oxygens. For the 23% protonated PEIs, indirect interaction mediated by one or more water molecules plays an important role in binding. Compared with the protonation state, the degree of branching has a smaller effect on binding, which essentially diminishes at the protonation ratio of 46%. These simulations shed light on the detailed mechanism(s) of PEI binding to DNA, and may facilitate the design of PEI-based gene delivery carriers.

Chemistry specificity of DNA–polycation complex salt response: a simulation study of DNA, polylysine and polyethyleneimine

“…and PEI50 binding to DNA reported here agree with previous simulational studies, 21,22 and experiments 59 where deprotonated PEI is was more prone to bind to DNA grooves, and it was suggested that this bind-ing is driven by the release of water. In contrast, protonated PEI preferred DNA backbone.…”

“…Monte Carlo simulations of PEI protonation confirm this configuration, 24 and similar choices for PEI protonation degree and configuration have previously been used for MD simulations of PEI. 21 The molecular structures of the polycations are shown in Fig. 1 First, the DNA strand was placed in a simulation box of 10×10×10 nm 3 together with two polycation molecules (two PLLs, PEI50s or PEI25s) and solvated with water.…”

“…In simulations, the more effective charge compensation by linear PEI compared to PLL 21 has been noted previously by Ziebarth and Wang. 22 Sun et al 21 indicated that an increase in branching has a similar effect in PEI binding to DNA as a decrease in charge per length.…”

Low Molecular Weight Branched PEI Binding to Linear DNA

“…26) Our molecular dynamics studies also showed that a 600 Da branched PEI binds to 4 base pairs in the major groove of DNA. 32) This corresponds to l=8, which was the parameter used in excluded site model in this study.…”

Effect of molecular weight of polyethyleneimine on loading of CpG oligodeoxynucleotides onto flake-shell silica nanoparticles for enhanced TLR9-mediated induction of interferon-α

“…These results suggest that PEI with a molecular weight of 800 Da cannot condense DNA efficiently. 46 Furthermore, Sun et al 47 reported that a high protonation ratio of the amino groups in PEI results in the formation of more stable complexes with DNA, but the degree of branching has lesser effect on DNA binding. The higher IFN-α production by flake-shell SiO 2 nanoparticles coated with PEI-600 is likely caused by increased affinity of CpG oligodeoxynucleotide molecules for TLR9, which results from the loose condensation of CpG oligodeoxynucleotide molecules.…”