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

Antila, Hanne S.; Härkönen, Marc; Sammalkorpi, Maria

doi:10.1039/c4cp04967e

Cited by 41 publications

(52 citation statements)

References 74 publications

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“…16,20,24,50 In general, these simulations have found that the nitrogen atoms of PEI chains with protonation states similar to the 50% protonation used here most commonly interact with the oxygen atoms of phosphate groups of the nucleic acid backbone and that interactions with electronegative atoms in the nucleic acid groove sites are much less prevalent. 16,18 Both the sequential addition and simultaneous addition simulations performed here agree with these results, as 85-90% of the direct interactions between a PEI nitrogen atom and an electronegative nucleic acid atom (i.e., the PEI nitrogen was within 3.5 Å of the nucleic acid atom) involved an O1P or O2P phosphate oxygen atom for both DNA and siRNA (Table 1). In many cases, the PEI chains are aligned with the major or minor grooves, enabling interaction with the phosphate groups on both sides of the groove, but they usually remain near the surface of the grooves and do not sufficiently penetrate the grooves to allow for direct interaction with electronegative groove atoms.…”

Section: Resultssupporting

confidence: 80%

“…15,17–22 Among other things, these studies have investigated how polyplexes formed from linear PEI differ from those formed with branched PEI, 20,23 how the addition of lipids to PEI impacts interactions with nucleic acids, 24 and the stability of polyplexes in response to high salt concentrations, similar to the environments that may be encountered by polyplexes along the gene delivery pathway. 18 …”

Section: Introductionmentioning

confidence: 99%

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Structural Comparisons of PEI/DNA and PEI/siRNA Complexes Revealed with Molecular Dynamics Simulations

et al. 2017

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Polyplexes composed of polyethyleneimine (PEI) and DNA or siRNA have attracted great attention for their use in gene therapy. While many physicochemical characteristics of these polyplexes remain unknown, PEI/DNA complexes have been repeatedly shown to be more stable than their PEI/siRNA counterparts. Here, we examine potential causes for this difference using atomistic molecular dynamics simulations of complexation between linear PEI and DNA or siRNA duplexes containing the same number of bases. The two types of polyplexes are stabilized by similar interactions, as PEI amines primarily interact with nucleic acid phosphate groups but also occasionally interact with groove atoms of both nucleic acids. However, the number of interactions in PEI/DNA complexes is greater than in comparable PEI/siRNA complexes, with interactions between protonated PEI amines and DNA being particularly enhanced. These results indicate that structural differences between DNA and siRNA may play a role in the increased stability of PEI/DNA complexes. Additionally, we investigate the binding of PEI chains to polyplexes that have a net positive charge. Binding of PEI to these overcharged complexes involves interactions between PEI and areas on the nucleic acid surface that have maintained a negative electrostatic potential and is facilitated by the release of water from the nucleic acid.

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Section: Resultssupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Structural Comparisons of PEI/DNA and PEI/siRNA Complexes Revealed with Molecular Dynamics Simulations

et al. 2017

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“…In both cases, we were unable to observe complete decomplexation during 700 ns; for PEI (protonation level 50%), this conclusion is in line with the findings of an earlier study. 23 However, we found that adding a divalent salt differently affects the average number of contacts between the phosphate groups of DNA and protonated amine groups for the two polymers: 6.2 ± 2.0 (8.9 ± 1.6) for PEI versus 2.2 ± 1.1 (2.8 ± 1.8) for PVA for systems with (without) a divalent salt. Therefore, it is seen that the response of a PVA−DNA complex to salt ions is indeed much weaker compared to that of a DNA complex with PEI, a linear cationic polymer of the same protonation level.…”

Section: ■ Discussion and Conclusionmentioning

confidence: 95%

Atomic-Scale Molecular Dynamics Simulations of DNA–Polycation Complexes: Two Distinct Binding Patterns

et al. 2016

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Synthetic cationic polymers represent a promising class of delivery vectors for gene therapy. Here, we employ atomistic molecular dynamics simulations to gain insight into the structure and properties of complexes of DNA with four linear polycations: polyethylenimine (PEI), poly-l-lysine (PLL), polyvinylamine (PVA), and polyallylamine (PAA). These polycations differ in their polymer geometries, protonation states, and hydrophobicities of their backbone chains. Overall, our results demonstrate for the first time the existence of two distinct patterns of binding of DNA with polycations. For PEI, PLL, and PAA, the complex is stabilized by the electrostatic attraction between protonated amine groups of the polycation and phosphate groups of DNA. In contrast, PVA demonstrates an alternative binding pattern as it gets embedded into the DNA major groove. It is likely that both the polymer topology and affinity of the backbone chain of PVA to the DNA groove are responsible for such behavior. The differences in binding patterns can have important biomedical implications: embedding PVA into a DNA groove makes it less sensitive to changes in the aqueous environment (pH level, ionic strength, etc.) and could therefore hinder the intracellular release of genetic material from a delivery vector, leading to lower transfection activity.

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“…All these effects in PE-ion systems, however, can be captured by particle level descriptions, such as Monte Carlo, or molecular dynamics (MD). Both, primitive numerical models in which the PEs are described as a rigid rod or a line charge with varying charge density 37,42,[48][49][50] and detailed all-atom simulations 20,46,51,52 have outlined the significance of chemistry specific effects via charge correlations. Specifically, the effect of ion species on the condensation of ions has been demonstrated in Refs.…”

Section: Introductionmentioning

confidence: 99%

Ability of the Poisson–Boltzmann equation to capture molecular dynamics predicted ion distribution around polyelectrolytes

Batys

Luukkonen

Sammalkorpi

2017

Phys. Chem. Chem. Phys.

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

Abstract: Molecular dynamics is used to study how polycation chemistry and charge per length affect the salt tolerance of DNA–polycation complexes.

Cited by 41 publications

References 74 publications

Structural Comparisons of PEI/DNA and PEI/siRNA Complexes Revealed with Molecular Dynamics Simulations

Structural Comparisons of PEI/DNA and PEI/siRNA Complexes Revealed with Molecular Dynamics Simulations

Atomic-Scale Molecular Dynamics Simulations of DNA–Polycation Complexes: Two Distinct Binding Patterns

Ability of the Poisson–Boltzmann equation to capture molecular dynamics predicted ion distribution around polyelectrolytes

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