Tailoring interleaflet lipid transfer with a DNA-based synthetic enzyme

Diana Sobota, Himanshu Joshi, Alexander Ohmann, Aleksei Aksimentiev, and Ulrich F. Keyser
Nano Letters 20(6) 4306-4311 (2020)
DOI:10.1021/acs.nanolett.0c00990  BibTex

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Lipid membranes, enveloping all living systems, are of crucial importance, and control over their structure and composition is a highly desirable functionality of artificial structures. However, the rational design of protein-inspired systems is still challenging. Here we have developed a highly functional nucleic acid construct that self-assembles and inserts into membranes, enabling lipid transfer between inner and outer leaflets. By designing the structure to account for interactions between the DNA, its hydrophobic modifications, and the lipids, we successfully exerted control over the rate of interleaflet lipid transfer induced by our DNA-based enzyme. Furthermore, we can regulate the level of lipid transfer by altering the concentration of divalent ions, similar to stimuli-responsive lipid-flipping proteins.

Abstract

Lipid membranes, enveloping all living systems, are of crucial importance, and control over their structure and composition is a highly desirable functionality of artificial structures. However, the rational design of protein-inspired systems is still challenging. Here we have developed a highly functional nucleic acid construct that self-assembles and inserts into membranes, enabling lipid transfer between inner and outer leaflets. By designing the structure to account for interactions between the DNA, its hydrophobic modifications, and the lipids, we successfully exerted control over the rate of interleaflet lipid transfer induced by our DNA-based enzyme. Furthermore, we can regulate the level of lipid transfer by altering the concentration of divalent ions, similar to stimuli-responsive lipid-flipping proteins.

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MD simulation of designed DNA duplex anchored in the DPhPE lipid bilayer membrane using 2 cholesterol molecules. The video illustrates ~ 1 µs all-atom MD simulation trajectory of the 0D system in explicit water and ions.  The complementary DNA strands are shown using turquoise and orange spheres and the backbone of DNA is shown in tubular representation. The lipid bilayer membrane is shown using turquoise lines and a representative carbon atom (C22) of the lipid headgroup is shown as turquoise and yellow spheres to distinguish the upper and lower leaflets respectively. The cholesterol molecules are shown in green, water and ions are not shown for the sake of clarity.  

MD simulation of DNA duplex decorated with a dodecane molecule (1D) and anchored in the DPhPE lipid bilayer membrane using 2 cholesterol molecules. The video illustrates ~ 1 µs all-atom MD simulation trajectory of the 1D system in explicit water and ions.  The complementary DNA strands are shown using turquoise and orange spheres and the backbone of DNA is shown in tubular representation. The lipid bilayer membrane is shown using turquoise lines and a representative carbon atom (C22) of the lipid headgroup is shown as turquoise and yellow spheres to distinguish the upper and lower leaflets respectively. The non-hydrogen atom of cholesterol and dodecane molecules are shown in green and magenta spheres respectively. Water and ions are not shown for the sake of clarity.

MD simulation of DNA duplex decorated with two dodecane molecules (2D) and anchored in the DPhPE lipid bilayer membrane using 2 cholesterol molecules. The video illustrates ~ 1 µs all-atom MD simulation trajectory of the 2D system in explicit water and ions.  The complementary DNA strands are shown using turquoise and orange spheres and the backbone of DNA is shown in tubular representation. The lipid bilayer membrane is shown using turquoise lines and a representative carbon atom (C22) of the lipid headgroup is shown as turquoise and yellow spheres to distinguish the upper and lower leaflets respectively. The non-hydrogen atom of cholesterol and dodecane molecules are shown in green and magenta spheres respectively. Water and ions are not shown for the sake of clarity.