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Hydrophobic Interactions between DNA Duplexes and Synthetic and Biological Membranes

Research output: Contribution to journalArticlepeer-review

Sioned F. Jones, Himanshu Joshi, Stephen J. Terry, Jonathan R. Burns, Aleksei Aksimentiev, Ulrike S. Eggert, Stefan Howorka

Original languageEnglish
Pages (from-to)8305-8313
Number of pages9
JournalJournal of the American Chemical Society
Issue number22
Accepted/In press2021
Published9 Jun 2021

Bibliographical note

Funding Information: We acknowledge funding by the Leverhulme Trust (RPG-2017-015, to U.E. and S.H.) and the Wellcome Trust (Investigator Award 110060/Z/15/Z, to U.E.). This work was supported by the Biotechnology and Biological Sciences Research Council (BB/J014567/1). A.A. and H.J. acknowledge support from the National Science Foundation USA (DMR-1827346), the Human Frontier Science Project (RGP0047/2020), and also the supercomputer time provided through the XSEDE allocation grant (MCA05S028) and the Blue Waters petascale supercomputer system (UIUC). Publisher Copyright: © Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


Equipping DNA with hydrophobic anchors enables targeted interaction with lipid bilayers for applications in biophysics, cell biology, and synthetic biology. Understanding DNA-membrane interactions is crucial for rationally designing functional DNA. Here we study the interactions of hydrophobically tagged DNA with synthetic and cell membranes using a combination of experiments and atomistic molecular dynamics (MD) simulations. The DNA duplexes are rendered hydrophobic by conjugation to a terminal cholesterol anchor or by chemical synthesis of a charge-neutralized alkyl-phosphorothioate (PPT) belt. Cholesterol-DNA tethers to lipid vesicles of different lipid compositions and charges, while PPT DNA binding strongly depends on alkyl length, belt position, and headgroup charge. Divalent cations in the buffer can also influence binding. Our MD simulations directly reveal the complex structure and energetics of PPT DNA within a lipid membrane, demonstrating that longer alkyl-PPT chains provide the most stable membrane anchoring but may disrupt DNA base paring in solution. When tested on cells, cholesterol-DNA is homogeneously distributed on the cell surface, while alkyl-PPT DNA accumulates in clustered structures on the plasma membrane. DNA tethered to the outside of the cell membrane is distinguished from DNA spanning the membrane by nuclease and sphingomyelinase digestion assays. The gained fundamental insight on DNA-bilayer interactions will guide the rational design of membrane-targeting nanostructures.

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