Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Weighing -- and imaging -- molecules one at a time


Building on their creation of the first-ever mechanical device that can measure the mass of individual molecules, one at a time, a team of Caltech scientists and their colleagues have created nanodevices that can also reveal their shape. Such information is crucial when trying to identify large protein molecules or complex assemblies of protein molecules.

"You can imagine that with large protein complexes made from many different, smaller subunits there are many ways for them to be assembled. These can end up having quite similar masses while actually being different species with different biological functions. This is especially true with enzymes, proteins that mediate chemical reactions in the body, and membrane proteins that control a cell's interactions with its environment," explains Michael Roukes, the Robert M. Abbey Professor of Physics, Applied Physics, and Bioengineering at Caltech and the co-corresponding author of a paper describing the technology that appeared March 30 in the online issue of the journal Nature Nanotechnology.

Multimode nanoelectromechanical systems (NEMS) based mass sensor; the main figure schematically depicts a doubly-clamped beam vibrating in fundamental mode (1). Conceptual "snapshots" of the first six vibrational modes are shown below (1-6), colors indicate high (red) to low (blue) strain. The inset shows a colorized electron micrograph of a piezoelectric NEMS resonator fabricated in Caltech's Kavli Nanoscience Institute.

Credit: M. Matheny, L.G. Villanueva, P. Hung, J. Li and M. Roukes/Caltech

One foundation of the genomics revolution has been the ability to replicate DNA or RNA molecules en masse using the polymerase chain reaction to create the many millions of copies necessary for typical sequencing and analysis. However, the same mass-production technology does not work for copying proteins. Right now, if you want to properly identify a particular protein, you need a lot of it -- typically millions of copies of just the protein of interest, with very few other extraneous proteins as contaminants. The average mass of this molecular population is then evaluated with a technique called mass spectrometry, in which the molecules are ionized -- so that they attain an electrical charge -- and then allowed to interact with an electromagnetic field. By analyzing this interaction, scientists can deduce the molecular mass-to-charge ratio.

But mass spectrometry often cannot discriminate subtle but crucial differences in molecules having similar mass-to-charge ratios. "With mass spectrometry today," explains Roukes, "large molecules and molecular complexes are first chopped up into many smaller pieces, that is, into smaller molecule fragments that existing instruments can handle. These different fragments are separately analyzed, and then bioinformatics--involving computer simulations -- are used to piece the puzzle back together. But this reassembly process can be thwarted if pieces of different complexes are mixed up together."

With their devices, Roukes and his colleagues can measure the mass of an individual intact molecule. Each device -- which is only a couple millionths of a meter in size or smaller -- consists of a vibrating structure called a nanoelectromechanical system (NEMS) resonator. When a particle or molecule lands on the nanodevice, the added mass changes the frequency at which the structure vibrates, much like putting drops of solder on a guitar string would change the frequency of its vibration and resultant tone. The induced shifts in frequency provide information about the mass of the particle. But they also, as described in the new paper, can be used to determine the three-dimensional spatial distribution of the mass: i.e., the particle's shape.

"A guitar string doesn't just vibrate at one frequency," Roukes says. "There are harmonics of its fundamental tone, or so-called vibrational modes. What distinguishes a violin string from a guitar string is really the different admixtures of these different harmonics of the fundamental tone. The same applies here. We have a whole bunch of different tones that can be excited simultaneously on each of our nanodevices, and we track many different tones in real time. It turns out that when the molecule lands in different orientations, those harmonics are shifted differently. We can then use the inertial imaging theory that we have developed to reconstruct an image in space of the shape of the molecule."

"The new technique uncovers a previously unrealized capability of mechanical sensors," says Professor Mehmet Selim Hanay of Bilkent University in Ankara, Turkey, a former postdoctoral researcher in the Roukes lab and co-first author of the paper. "Previously we've identified molecules, such as the antibody IgM, based solely on their molecular weights. Now, by enabling both the molecular weight and shape information to be deduced for the same molecule simultaneously, the new technique can greatly enhance the identification process, and this is of significance both for basic research and the pharmaceutical industry."

Currently, molecular structures are deciphered using X-ray crystallography, an often laborious technique that involves isolating, purifying, and then crystallizing molecules, and then evaluating their shape based on the diffraction patterns produced when x-rays interact with the atoms that together form the crystals. However, many complex biological molecules are difficult if not impossible to crystallize. And, even when they can be crystallized, the molecular structure obtained represents the molecule in the crystalline state, which can be very different from the structure of the molecule in its biologically active form.

"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," Roukes says. In these cases, the ability to carry out single-molecule detection and to get as many separate bits of information as possible about that individual molecule greatly improves the odds of making a unique identification.

"We say that cancer begins often with a single aberrant cell, and what that means is that even though it might be one of a multiplicity of similar cells, there is something unique about the molecular composition of that one cell. With this technique, we potentially have a new tool to figure out what is unique about it," he adds.

So far, the new technique has been validated using particles of known sizes and shapes, such as polymer nanodroplets. Roukes and colleagues show that with today's state-of-the-art nanodevices, the approach can provide molecular-scale resolution -- that is, provide the ability to see the molecular subcomponents of individual, intact protein assemblies. The group's current efforts are now focused on such explorations.


Scott Kelber, a former graduate student in the Roukes lab, is the other co-first author of the paper, titled "Inertial imaging with nanoelectromechanical systems." Professor John Sader of the University of Melbourne, Australia, and a visiting associate in physics at Caltech, is the co-corresponding author. Additional coauthors are Cathal D. O'Connell and Paul Mulvaney of the University of Melbourne.

Brian Bell | EurekAlert!

Further reports about: Caltech Weighing ability fragments nanodevices pieces proteins structure

More articles from Physics and Astronomy:

nachricht Mars 2020 mission to use smart methods to seek signs of past life
17.08.2017 | Goldschmidt Conference

nachricht Gold shines through properties of nano biosensors
17.08.2017 | American Institute of Physics

All articles from Physics and Astronomy >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>



Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

Latest News

Gold shines through properties of nano biosensors

17.08.2017 | Physics and Astronomy

Greenland ice flow likely to speed up: New data assert glaciers move over sediment, which gets more slippery as it gets wetter

17.08.2017 | Earth Sciences

Mars 2020 mission to use smart methods to seek signs of past life

17.08.2017 | Physics and Astronomy

More VideoLinks >>>