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DNA Lipoplexes: Formation of the Inverse Hexagonal Phase Observed by Coarse-Grained Molecular Dynamics Simulation

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† School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1 BJ, United Kingdom
‡ Membrane Biophysics Platform, Department of Chemistry, Imperial College, London, SW7 2AZ United Kingdom
*To whom correspondence should be addressed. Mailing address: School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1 BJ, U.K. Telephone: +442380591476. E-mail: [email protected]
Cite this: Langmuir 2010, 26, 14, 12119–12125
Publication Date (Web):June 28, 2010
https://doi.org/10.1021/la101448m
Copyright © 2010 American Chemical Society
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    Abstract

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    Mixtures of dsDNA and lipids, so-called lipoplexes, are widely used as less toxic alternatives to viral vectors in transfection studies. However, the transfection efficiency achieved by lipoplexes is significantly lower than that of viral vectors and is a barrier to their use in the clinic. There is now significant evidence suggesting that the molecular organization and structure (nanoarchitecture) of lipoplexes might correlate with biological activity. As a consequence, the ability to predict quantitatively the nanoarchitecture of new systems, and how these might change intracellularly, would be a major tool in the development of rational discovery strategies for more efficient lipoplex formulations. Here we report the use of a coarse-grain molecular dynamics simulation to predict the phases formed by two lipoplex systems: dsDNA−DOPE and dsDNA−DOPE−DOTAP. The predictions of the simulations show excellent agreement with experimental data from polarized light microscopy and small-angle X-ray diffraction (SAXS); the simulations predicted the formation of phases with d-spacings that were comparable to those measured by SAXS. More significantly, the simulations were able to reproduce for the first time the experimentally observed change from a fluid lamellar to an inverse hexagonal phase in the dsDNA−DOPE−DOTAP system as a function of changes in lipid composition. Our studies indicate that coarse-grain MD simulations could provide a powerful tool to understand, and hence design, new lipoplex systems.

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    One figure describing how the d-spacings were calculated from simulations; one plot showing movement of water molecules within the inverse hexagonal channels; one figure showing the structures of the CG lipid molecules; one figure showing interdigitation of ions between lipid headgroups; one experimental phase diagram; one table summarizing simulation systems. This material is available free of charge via the Internet at http://pubs.acs.org.

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