Nature Communications | 2025 Oct 2|16(1):8666| doi: 10.1038/s41467-025-64025-6
Neilah Firzan Ca, Kalyanashis Jana, Sreelakshmi Radhakrishnan, Rifat Aara, Mubeena S, Radhika Nair, Harsha Bajaj, Ulrich Kleinekathöfer, Kozhinjampara R Mahendran
Synthetic nanopores composed of mirror-image peptides have been reported, but not fully functional mirror-image pores. Here, we construct a monodisperse mirror-image nanopore, DpPorA and characterise its functional properties. Importantly, we alter the charge pattern and assemble a superior mirror-image pore with enhanced conductance and selectivity under different salt conditions. This pore is used for single-molecule sensing of structurally divergent biomolecules, including peptides, PEGylated polypeptides, full-length alpha-synuclein protein and cyclic sugars. Molecular dynamics simulations confirm these DpPorA are exact mirror-images of LpPorA, further revealing their structurally stable conformation. Fluorescence imaging of giant vesicles reconstituted with mirror-image peptides reveals the formation of large flexible pores facilitating size-dependent molecular transport. To explore biomedical applications, the differential cytotoxic effect of mirror-image peptides and their fluorescently tagged forms on cancer cells demonstrates a significant effect on membrane disruption and cell viability, as opposed to no effect on normal cells. We emphasize that this class of mirror-image pores can advance the development of molecular sensors and therapeutics.
