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Dynamic Interactions between Lipid-Tethered DNA and Phospholipid Membranes

  • Patrick M. Arnott
    Patrick M. Arnott
    Department of Chemistry, Institute of Structural and Molecular Biology, University College London, London WC1H 0AJ, United Kingdom
  • Himanshu Joshi
    Himanshu Joshi
    Department of Physics, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
  • Aleksei Aksimentiev*
    Aleksei Aksimentiev
    Department of Physics, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
    *E-mail: [email protected]
  • , and 
  • Stefan Howorka*
    Stefan Howorka
    Department of Chemistry, Institute of Structural and Molecular Biology, University College London, London WC1H 0AJ, United Kingdom
    *E-mail: [email protected]
Cite this: Langmuir 2018, 34, 49, 15084–15092
Publication Date (Web):October 10, 2018
https://doi.org/10.1021/acs.langmuir.8b02271
Copyright © 2018 American Chemical Society

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    Abstract

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    Lipid-anchored DNA can attach functional cargo to bilayer membranes in DNA nanotechnology, synthetic biology, and cell biology research. To optimize DNA anchoring, an understanding of DNA–membrane interactions in terms of binding strength, extent, and structural dynamics is required. Here we use experiments and molecular dynamics (MD) simulations to determine how the membrane binding of cholesterol-modified DNA depends on electrostatic and steric factors involving the lipid headgroup charge, duplexed or single-stranded DNA, and the buffer composition. The experiments distinguish between free and membrane vesicle-bound DNA and thereby reveal the surface density of anchored DNA and its binding affinity, something which had previously not been known. The Kd values range from 8.5 ± 4.9 to 466 ± 134 μM whereby negatively charged headgroups led to weak binding due to the electrostatic repulsion with respect to the negatively charged DNA. Atomistic MD simulations explain the findings and elucidate the dynamic nature of anchored DNA such as the mushroom-like conformation of single-stranded DNA hovering over the bilayer surface in contrast to a straight-up conformation of double-stranded DNA. The biophysical insight into the binding strength to membranes as well as the molecular accessibility of DNA for hybridization to molecular cargo is expected to facilitate the creation of biomimetic DNA versions of natural membrane nanopores and cytoskeletons for research and nanobiotechnology.

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.langmuir.8b02271.

    • A table with the values of maximum surface density and Kd obtained from the gel shift assay; a histogram summarizing the values of maximum surface density and Kd obtained from the gel shift assay; molecular graphics images illustrating the conformations of dsDNA and ssDNA molecules observed in MD simulations; graphs detailing the effect of the ion type on screening the charge of a PE/PG membrane; additional molecular graphic images illustrating representative conformations of tethered DNA; graphs illustrating the dependence of the following quantities on the simulation time: the average tilt of the DNA molecules, the fraction of DNA in contact with the membrane, the distance between cholesterol and membrane, the distance between the membrane and DNA, the distance between cholesterol and the membrane, and the mean-squared displacement of the cholesterol anchor (PDF)

    • All-atom molecular dynamics simulation of dsDNA molecules cholesterol-anchored to a POPE lipid bilayer membrane (MPG)

    • All-atom molecular dynamics simulation of dsDNA molecules cholesterol-anchored to a lipid membrane composed of a 50/50 mixture of POPE and POPG lipids (MPG)

    • All-atom molecular dynamics simulation of dsDNA molecules cholesterol-anchored to a lipid membrane composed of a 50/50 mixture of POPE and POPC lipids (MPG)

    • All-atom molecular dynamics simulation of ssDNA molecules cholesterol-anchored to a POPE lipid bilayer membrane (MPG)

    • All-atom molecular dynamics simulation of ssDNA molecules cholesterol-anchored to a lipid membrane composed of a 50/50 mixture of POPE and POPG lipids (MPG)

    • All-atom molecular dynamics simulation of ssDNA molecules cholesterol-anchored to a lipid membrane composed of a 50/50 mixture of POPE and POPC lipids (MPG)

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