De novo design of nanopores for single-molecule detection that incorporates α-helix peptides

02 February 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Nanopore sensing using transmembrane proteins enjoys great potential for rapid and low-cost single-molecule detection. Creating pore-forming proteins or peptides is an emerging frontier in the field of nanopore sensing. One of the approaches for constructing new nanopores is bottom-up De novo protein design. Due to the difficulties in designing and expressing transmembrane proteins, peptides are the first design target, but so far, de novo α-helical nanopores with sizes large enough to transport biomolecules have not been reported. Here, we constructed α-helical nanopores based on GX6G and GX3G motifs, named FFK and LEK. FFK formed multidisperse pores with diameters of 0.9 to 1.4 nm while LEK formed monodisperse pores with a diameter of 0.9 nm. Though the larger diameter of FFK nanopores provides opportunities for molecular translocation, the too-fast join and dissociate of peptide monomers make them unsuited for nanopore sensing. On the other hand, translocation of poly-L-lysine through LEK nanopore could be observed by electrical recording, revealing their possibility for amino-acid sequencing. Our findings provide new opportunities to create designer nanopores for nanopore sensing technologies.


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