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Mathematics Professor John Sader from the University of Melbourne worked with California Institute of Technology experimentalists to invent a new method to weigh and image single molecules.

CREDIT: Photo: Peter Casamento

Abstract:
A microscopic tool, more than 1000 times thinner than the width of a single human hair, uses vibrations to simultaneously reveal the mass and the shape of a single molecule - a feat which has not been possible until now.

Scientists join forces to reveal the mass and shape of single molecules

Melbourne, Australia | Posted on April 27th, 2015

The work was led by Professor John Sader at the University of Melbourne's School of Mathematics and Statistics and Professor Michael Roukes of the California Institute of Technology. It features in a paper published in this month's issue of Nature Nanotechnology.

Prof Sader says this technique revolutionises molecule detection for biologists, or indeed anyone who wants to measure extremely small objects.

To discover what a specimen looks like, researchers attach it to a tiny vibrating device, known as a nanoelectromechanical system (NEMS) resonator.

"One standard way to tell the difference between molecules is to weigh them using a technique called mass spectrometry. The problem is that different molecules can have the same weight. Now, we can tell them apart by identifying their shape," Prof Sader said.

"This technology is built on a new mathematical algorithm that we developed, called inertial imaging. It can be used as a diagnostic tool if you're trying to identify, say, a virus or a bacteria particle."

In mass spectrometry, molecules are ionised (or electrically charged) so that an electromagnetic field can interact with them. This interaction is then measured, which gives vital information on the molecule's mass-to-charge ratio.

But this conventional technique has difficulty telling the difference between molecules with similar mass-to-charge ratios, meaning molecule A and molecule B might be very different, but mass-spectrometry can't see this difference.

"But when a molecule lands on a vibrating NEMS device, this extra mass reduces the many vibration frequencies of the device. The way the frequencies change depends on the mass and shape of the molecule, so we can now tell a lot about how it looks and how much it weighs," Prof Sader added.

It's a lot like attaching a drop of solder on the string of a guitar - it changes its vibration frequency and also its tone.

"We can analyse this measurement to get both the mass and shape of the attached particle," Prof Sader said.

"This is very different to an optical microscope, where light limits the size you can measure. This so-called 'diffraction limit' plays no part in this new technology."

A common way to decipher molecular structures is to use x-ray crystallography. This complicated method involves purifying and crystallising the molecules, then firing x-rays through the sample and interpreting the resulting patterns. However, this is also problematic because the structure of a molecule in its natural environment can be different.

California Institute of Technology Professor Michael Roukes says NEMS and inertial imaging could prove very useful for biological scientists.

"You can imagine situations where you don't know exactly what you are looking for, where you are in discovery mode, and you are trying to figure out the body's immune response to a particular pathogen, for example," Prof Roukes said.

"This new technique adds another piece of information to aid our identification of molecules, but now at the single molecule level, which could prove useful in biomedical applications, among other uses."

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Co-authors on the Inertial imaging with nanoelectromechanical systems paper include Mehmet Selim Hanay, Scott Kelber of Caltech and Cathal D. O'Connell and Paul Mulvaney of the School of Chemistry and Bio21 Institute at the University of Melbourne.

The work was funded by a National Institutes of Health Director's Pioneer award, a Caltech Kavli Nanoscience Institute Distinguished Visiting Professorship, the Fondation pour la Recherche et l'Enseignement Superieur in Paris, and the Australian Research Council grants scheme.