École polytechnique fédérale de Lausanne (EPFL) researchers have achieved near-perfect control over the manipulation of individual molecules, allowing them to be identified and characterized with unprecedented precision

Background: A nanopore is a nanometer-sized hole formed in a synthetic membrane. It can be used for experimental direct sequencing of a single DNA molecule. As the DNA molecule passes through the nanopore, the passage causes changes in the ion current. Those changes can be used to determine the desired sequence of nucleotides (which encode genetic information) by analyzing how each nucleotide perturbs this current as it passes through. 

However, the passage of molecules through a nanopore and the timing of their analysis are influenced by random physical forces, making it difficult to achieve high analytical accuracy.

Advanced sensing precision

So Aleksandra Radenovic, head of the EPFL Laboratory of Nanoscale Biology in the School of Engineering, has “combined the sensitivity of nanopores with the precision of a scanning ion conductance microscopy (SICM) device.”

This innovation allows for controlling molecule transit speed through the nanopore, allowing thousands of consecutive readings to be taken of the same molecule, and even of different locations on the molecule, she noted.

It can also average multiple readings of the same molecule, which has resulted in an increase in signal-to-noise ratio of two orders of magnitude, compared to conventional methods, the scientists report.

Opens up use in peptide sequencing

“This exquisite control could help fill a big gap in the field,” said Radenovic. “This precision and versatility also mean that the approach could be applied to molecules beyond DNA, such as protein building blocks called peptides, which could help advance proteomics as well as biomedical and clinical research.

“Finding a solution for sequencing peptides has been a significant challenge due to the complexity of their ‘license plates,’ which are made up of 20 characters (amino acids) as opposed to DNA’s four nucleotides,” says Radenovic.”For me, the most exciting hope is that this new control might open an easier path ahead to peptide sequencing.”

Citation: Leitao, S. M., Navikas, V., Miljkovic, H., Drake, B., Marion, S., Pistoletti Blanchet, G., Chen, K., Mayer, S. F., Keyser, U. F., Kuhn, A., Fantner, G. E., & Radenovic, A. (2023). Spatially multiplexed single-molecule translocations through a nanopore at controlled speeds. Nature Nanotechnology, 1-7. https://doi.org/10.1038/s41565-023-01412-4

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