A Scale for Weighing Single Molecules

Imagine a scale that can weigh a single molecule, with a precision measured in the mass of a proton. California Institute of Technology researchers have built it: a digital device that can weigh single proteins (or nanoparticles) as small as 1 megaDalton (about 1.6 attogram).

Using standard CMOS manufacturing techniques, Michael L. Roukes’s Nanoscale Systems lab (in collaboration with CEA-LETI in Grenoble) fabricated what they call a nanoelectromechanical systems-based mass spectrometer (NEMS-MS), a vibrating-beam scale less than 10 micrometers long.  (They describe the device in the current issue of Nature Nanotechnology.)

Nanoelectromechanical Mass Spectrometer (Caltech)In the colorized scanning electron micrograph, the weighing beam is the narrow strip running from upper left to lower right. The dashed white lines show where the device is bonded to the substrate. The yellow regions are aluminum/silicon contacts for driving the capacitative gates that make the beam vibrate from side to side.

Using a feedback loop, implemented with a General Purpose Interface Bus (GPIB) protocol, the group made the beam resonate to its first and second harmonics simultaneously.  The narrow supporting struts near the beam-ends flex with the beam’s motion; the strain changes the strut’s electrical resistance, allowing direct measurement of the vibration.

The researchers use conventional “soft” mass-spectrometry vaporization techniques—matrix-assisted laser desorption ionization and electrospray ionization—to produce a beam of single molecules or nanoparticles without breaking them apart.  At this scale and temperature (about 80 K, or -193 C), van der Waals forces firmly glue incident analyte ions to the oscillating beam. The added mass reduces the resonant frequency. (Sticking a wad of chewing gum to a vibrating guitar string would produce the same effect.)  The graph of resonant-mode frequency over time looks like a staircase. It shows a nearly instantaneous frequency drop as each incoming molecule strikes and sticks to the vibrating beam.

There’s a catch, though: the precise frequency change depends on the particle’s mass and its position.

The Roukes group (including the lead authors, postdoc Mehmet Selim Hanay and grad student Scott Kelber) realized that the mass-and-position frequency change would be different for different resonant modes. By plotting the changes in the first and second modes against one another, the Caltech team can calculate the mass of the stuck-on molecule to within 50 to 100 kDA.

Though the method can theoretically measure masses down to an accuracy of about one Dalton, noise in the system limits the smallest frequency change the device can detect. In their first demonstration, Roukes et al. used the NEMS-MS device to weigh gold nanoparticles (10 and 5 nanometers in diameter, roughly 6.7 MDa and 0.8 MDa, respectively) and single molecules of human immunoglobulin M (IgM, which forms multimers that weighed in at about 1.03 MDa to 2.09 MDa, within 7% or less of the mass predicted from their protein sequences).

Image: California Institute of Technology

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