Morzy, DianaJoshi, HimanshuSandler, Sarah E.Aksimentiev, AlekseiKeyser, Ulrich F.2022-03-142022-03-142022-03-142021-11-2410.1021/acs.nanolett.1c03791https://infoscience.epfl.ch/handle/20.500.14299/186345WOS:000756421600054DNA 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 membrane 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 can cause fraying of terminal base pairs of nicked DNA constructs, distorting them when embedded in a lipid bilayer. Importantly, we show that DNA nanostructures with no backbone discontinuities form more stable conductive pores and insert into membranes with a higher efficiency than the equivalent nicked constructs. Moreover, lack of nicks allows design and maintenance of membrane-spanning helices in a tilted orientation within the lipid bilayer. Thus, reducing the conformational degrees of freedom of the DNA nanostructures enables better control over their function as synthetic ion channels.Chemistry, MultidisciplinaryChemistry, PhysicalNanoscience & NanotechnologyMaterials Science, MultidisciplinaryPhysics, AppliedPhysics, Condensed MatterChemistryScience & Technology - Other TopicsMaterials SciencePhysicsdna structureslipid membranestiltnicksprotein-mimickingsynthetic ion channellipid-bilayerhydrophobic mismatchchain-lengthcholesterolnanostructuresdeterminantsliposomestransportnanoporesstackingtext::journal::journal article::research article