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Computational insights into the interactions between DNA and siRNA with "rigid" and "flexible" triazine dendrimers.

ABSTRACT: In this study, simulation challenges intuitive models of "flexible" and "rigid" generation two triazine dendrimers as it pertains to solution conformation and conformation on binding DNA or siRNA sequences. These results derive from structural and energetic analyses of the binding events. Simulations of the rigid structure reinforce the role of the constrained piperazine linker in positioning the peripheral groups at significant distance from each other and the core of the dendrimer. In contrast, the flexible dendrimer, characterized by triethyleneglycol-like linkers, collapses in solution. On binding DNA and siRNA, these conformations are largely retained. The rigid dendrimer undergoes reorganization of peripheral groups to generate a large number of contacts to the nucleic acid. In contrast, the flexible dendrimer, originally conceived to create multivalent interactions with nucleic acids, generates only a few contacts and collapses further. This paper provides unique insight in the role played by molecular flexibility in the binding phenomenon.

SUBMITTER: Pavan GM

PROVIDER: S-EPMC3841066 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Computational insights into the interactions between DNA and siRNA with "rigid" and "flexible" triazine dendrimers.

Pavan Giovanni M GM Mintzer Meredith A MA Simanek Eric E EE Merkel Olivia M OM Kissel Thomas T Danani Andrea A

Biomacromolecules 20100301 3

In this study, simulation challenges intuitive models of "flexible" and "rigid" generation two triazine dendrimers as it pertains to solution conformation and conformation on binding DNA or siRNA sequences. These results derive from structural and energetic analyses of the binding events. Simulations of the rigid structure reinforce the role of the constrained piperazine linker in positioning the peripheral groups at significant distance from each other and the core of the dendrimer. In contrast ...[more]

PMID: 20131771

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Project description:This study aimed to identify suitable siRNA delivery systems based on flexible generation 2-4 triazine dendrimers by correlating physico-chemical and biological in vitro and in vivo properties of the complexes with thermodynamic parameters calculated using molecular modeling. The siRNA binding properties of the dendrimers and PEI 25 kDa were simulated, binding and stability were measured in SYBR Gold assays, and hydrodynamic diameters, zeta potentials, and cytotoxicity were quantified. These parameters were compared with cellular uptake of the complexes and their ability to mediate RNAi. Radiolabeled complexes were administered intravenously, and pharmacokinetic profiles and biodistribution of these polyplexes were assessed both invasively and non-invasively. All flexible triazine dendrimers formed thermodynamically more stable complexes than PEI. While PEI and the generation 4 dendrimer interacted more superficially with siRNA, generation 2 and 3 virtually coalesced with siRNA, forming a tightly intertwined structure. These dendriplexes were therefore more efficiently charge-neutralized than PEI complexes, reducing agglomeration. This behavior was confirmed by results of hydrodynamic diameters (72.0 nm-153.5 nm) and zeta potentials (4.9 mV-21.8 mV in 10 mM HEPES) of the dendriplexes in comparison to PEI complexes (312.8 nm-480.0 nm and 13.7 mV-17.4 mV in 10 mM HEPES). All dendrimers, even generation 3 and 4, were less toxic than PEI. All dendriplexes were efficiently endocytosed and showed significant and specific luciferase knockdown in HeLa/Luc cells. Scintillation counting confirmed that the generation 2 triazine complexes showed more than twofold prolonged circulation times as a result of their good thermodynamic stability. Conversely, generation 3 complexes dissociated in vivo, and generation 4 complexes were captured by the reticulo-endothelial system due to their increased surface charge. Molecular modeling proves very valuable for rationalizing experimental parameters based on the dendrimers' structural properties. Non-invasive molecular imaging predicted the in vivo fate of the complexes. Therefore, both techniques effectively promote the rapid development of safe and efficient siRNA formulations that are stable in vivo.

Dataset Information

Computational insights into the interactions between DNA and siRNA with "rigid" and "flexible" triazine dendrimers.

Publications

Computational insights into the interactions between DNA and siRNA with "rigid" and "flexible" triazine dendrimers.

Similar Datasets

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