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Membrane activity of a DNA-based ion channel depends on the stability of its double-stranded structure

View ORCID ProfileDiana Morzy, View ORCID ProfileHimanshu Joshi, View ORCID ProfileSarah E. Sandler, View ORCID ProfileAleksei Aksimentiev, View ORCID ProfileUlrich F. Keyser
doi: https://doi.org/10.1101/2021.07.11.451603
Diana Morzy
1Cavendish Laboratory, University of Cambridge, JJ Thomson Avenue, Cambridge, CB3 0HE, United Kingdom
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Himanshu Joshi
2Department of Physics, University of Illinois at Urbana–Champaign, 1110 West Green Street, Urbana, Illinois 61801, United States
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Sarah E. Sandler
1Cavendish Laboratory, University of Cambridge, JJ Thomson Avenue, Cambridge, CB3 0HE, United Kingdom
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Aleksei Aksimentiev
2Department of Physics, University of Illinois at Urbana–Champaign, 1110 West Green Street, Urbana, Illinois 61801, United States
3Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, 405 North Mathews Avenue, Urbana, Illinois 61801, United States
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  • For correspondence: ufk20@cam.ac.uk aksiment@illinois.edu
Ulrich F. Keyser
1Cavendish Laboratory, University of Cambridge, JJ Thomson Avenue, Cambridge, CB3 0HE, United Kingdom
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  • For correspondence: ufk20@cam.ac.uk aksiment@illinois.edu
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Abstract

Structural DNA nanotechnology has emerged as a promising method for designing spontaneously-inserting and fully-controllable synthetic ion channels. However, both insertion efficiency and stability of existing DNA-based ion channels leave much room for improvement. Here, we demonstrate an approach to overcoming the unfavorable DNA-lipid interactions that hinder the formation of a stable transmembrane pore. Our all-atom MD simulations and experiments show that the insertion-driving cholesterol modifications, when introduced at an end of a DNA strand, are likely to cause fraying of the terminal base pairs as the DNA nanostructure adopts its energy-minimum configuration in the membrane. We also find that fraying of base pairs distorts nicked DNA constructs when embedded in a lipid bilayer. Here, we show that DNA nanostructures that do not have discontinuities (nicks) in their DNA backbones form considerably more stable DNA-induced conductive pores and insert into lipid membranes with a higher efficiency than the equivalent nicked constructs. Moreover, lack of nicks allows to design and maintain membrane-spanning helices in a tilted orientation within lipid bilayer. Thus, reducing the conformational degrees of freedom of the DNA nanostructures enables better control over their function as synthetic ion channels.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted July 12, 2021.
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Membrane activity of a DNA-based ion channel depends on the stability of its double-stranded structure
Diana Morzy, Himanshu Joshi, Sarah E. Sandler, Aleksei Aksimentiev, Ulrich F. Keyser
bioRxiv 2021.07.11.451603; doi: https://doi.org/10.1101/2021.07.11.451603
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Membrane activity of a DNA-based ion channel depends on the stability of its double-stranded structure
Diana Morzy, Himanshu Joshi, Sarah E. Sandler, Aleksei Aksimentiev, Ulrich F. Keyser
bioRxiv 2021.07.11.451603; doi: https://doi.org/10.1101/2021.07.11.451603

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