Multi-Scanning Individual Molecules for Extreme Precision

Multi-Scanning Individual Molecules for Extreme Precision

EPFL researchers led by Dr. Aleksandra Radenovic have superior nanopore know-how by integrating it with scanning ion conductance microscopy. The resultant method, scanning ion conductance spectroscopy, presents unprecedented precision in controlling molecular transit velocity, yielding a major signal-to-noise ratio enhance. This versatile methodology may vastly affect DNA evaluation, proteomics, and medical analysis. Credit score: Samuel Leitão / EPFL

EPFL researchers have achieved near-perfect management over the manipulation of particular person molecules, permitting them to be recognized and characterised with unprecedented precision.

Aleksandra Radenovic, head of the Laboratory of Nanoscale Biology within the Faculty of Engineering, has labored for years to enhance nanopore know-how, which includes passing a molecule like DNA through a tiny pore in a membrane to measure an ionic current. Scientists can determine DNA’s sequence of nucleotides – which encodes genetic information – by analyzing how each one perturbs this current as it passes through. The research was published on June 19 in the journal Nature Nanotechnology.

Currently, the passage of molecules through a nanopore and the timing of their analysis are influenced by random physical forces, and the rapid movement of molecules makes achieving high analytical accuracy challenging. Radenovic has previously addressed these issues with optical tweezers and viscous liquids. Now, a collaboration with Georg Fantner and his team in the Laboratory for Bio- and Nano-Instrumentation at EPFL has yielded the advancement she’s been looking for – with results that could go far beyond DNA. 

Extreme DNA Resolution

By combining nanopore technology with scanning ion conductance microscopy for the first time, EPFL researchers have achieved near-perfect control over the manipulation of individual molecules, allowing them to be identified and characterized with unprecedented precision. Credit: Samuel Leitão / EPFL

“We have combined the sensitivity of nanopores with the precision of scanning ion conductance microscopy (SICM), allowing us to lock onto specific molecules and locations and control how fast they move. This exquisite control could help fill a big gap in the field,” Radenovic says. The researchers achieved this control using a repurposed state-of-the-art scanning ion conductance microscope, recently developed at the Lab for Bio- and Nano-Instrumentation. 

Improving sensing precision by two orders of magnitude

The serendipitous collaboration between the labs was catalyzed by PhD student Samuel Leitão. His research focuses on SICM, in which variations in the ionic current flowing through a probe tip are used to produce high-resolution 3D image data. For his PhD, Leitão developed and applied SICM technology to the imaging of nanoscale cell structures, using a glass nanopore as the probe. In this new work, the team applied a SICM probe’s precision to moving molecules through a nanopore, rather than letting them diffuse through randomly.

Dubbed scanning ion conductance spectroscopy (SICS), the innovation slows molecule transit through the nanopore, allowing thousands of consecutive readings to be taken of the same molecule, and even of different locations on the molecule. The ability to control transit speed and average multiple readings of the same molecule has resulted in an increase in signal-to-noise ratio of two orders of magnitude compared to conventional methods.

By combining nanopore know-how with scanning ion conductance microscopy for the primary time, EPFL researchers have achieved near-perfect management over the manipulation of particular person molecules, permitting them to be recognized and characterised with unprecedented precision. Credit score: Samuel Leitão / EPFL

“What’s significantly thrilling is that this elevated detection functionality with SICS could also be transferable to different solid-state and organic nanopore strategies, which may considerably enhance diagnostic and sequencing purposes,” Leitão says.

Fantner summarizes the logic of the strategy with an automotive analogy: “Think about you might be watching automobiles drive forwards and backwards as you stand in entrance of a window. It’s quite a bit simpler to learn their license plate numbers if the automobiles decelerate and drive by repeatedly,” he says. “We additionally get to resolve if we wish to measure 1,000 totally different molecules every one time or the identical molecule 1,000 instances, which represents an actual paradigm shift within the area.”

This precision and flexibility imply that the strategy may very well be utilized to molecules past DNA, equivalent to protein constructing blocks referred to as peptides, which may assist advance proteomics in addition to biomedical and medical analysis.

“Discovering an answer for sequencing peptides has been a major problem as a result of complexity of their “license plates”, that 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.”

Reference: “Spatially multiplexed single-molecule translocations through a nanopore at controlled speeds” by S. M. Leitao, V. Navikas, H. Miljkovic, B. Drake, S. Marion, G. Pistoletti Blanchet, K. Chen, S. F. Mayer, U. F. Keyser, A. Kuhn, G. E. Fantner and A. Radenovic, 19 June 2023, Nature Nanotechnology.
DOI: 10.1038/s41565-023-01412-4

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