Article | Published:

Single-protein nanomechanical mass spectrometry in real time

Nature Nanotechnology volume 7, pages 602608 (2012) | Download Citation

Abstract

Nanoelectromechanical systems (NEMS) resonators can detect mass with exceptional sensitivity. Previously, mass spectra from several hundred adsorption events were assembled in NEMS-based mass spectrometry using statistical analysis. Here, we report the first realization of single-molecule NEMS-based mass spectrometry in real time. As each molecule in the sample adsorbs on the resonator, its mass and position of adsorption are determined by continuously tracking two driven vibrational modes of the device. We demonstrate the potential of multimode NEMS-based mass spectrometry by analysing IgM antibody complexes in real time. NEMS-based mass spectrometry is a unique and promising new form of mass spectrometry: it can resolve neutral species, provide a resolving power that increases markedly for very large masses, and allow the acquisition of spectra, molecule-by-molecule, in real time.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Mass spectrometric studies on amino acid and peptide derivatives. Acta Chem. Scand. 12, 1353 (1958).

  2. 2.

    The use of the mass spectrometer for the identification of organic compounds. Microchim. Acta 44, 437–453 (1956).

  3. 3.

    & Mass spectrometry and protein analysis. Science 312, 212–217 (2006).

  4. 4.

    & Mass spectrometry of macromolecular assemblies: preservation and dissociation. Curr. Opin. Struct. Biol. 16, 245–251 (2006).

  5. 5.

    , , & Protein complexes in the gas phase: technology for structural genomics and proteomics. Chem. Rev. 107, 3544–3567 (2007).

  6. 6.

    , & New dimensions in the study of protein complexes using quantitative mass spectrometry. FEBS Lett. 583, 1674–1683 (2009).

  7. 7.

    , , , & Chaperonin complexes monitored by ion mobility mass spectrometry. J. Am. Chem. Soc. 131, 1452–1459 (2009).

  8. 8.

    Native mass spectrometry: a bridge between interactomics and structural biology. Nature Methods 5, 927–933 (2008).

  9. 9.

    , & Ultrasensitive nanoelectromechanical mass detection. Appl. Phys. Lett. 84, 4469–4471 (2004).

  10. 10.

    et al. Attogram detection using nanoelectromechanical oscillators. J. Appl. Phys. 95, 3694–3703 (2004).

  11. 11.

    , , , & Zeptogram-scale nanomechanical mass sensing. Nano Lett. 6, 583–586 (2006).

  12. 12.

    , & Ultra-sensitive NEMS-based cantilevers for sensing, scanned probe and very high-frequency applications. Nature Nanotech. 2, 114–120 (2007).

  13. 13.

    , , & Atomic-scale mass sensing using carbon nanotube resonators. Nano Lett. 8, 4342–4346 (2008).

  14. 14.

    , , & Ultrasensitive mass sensing with a nanotube electromechanical resonator. Nano Lett. 8, 3735–3738 (2008).

  15. 15.

    , & An atomic-resolution nanomechanical mass sensor. Nature Nanotech. 3, 533–537 (2008).

  16. 16.

    , , , & Towards single-molecule nanomechanical mass spectrometry. Nature Nanotech. 4, 445–450 (2009).

  17. 17.

    et al. Nanomechanical mass sensing and stiffness spectrometry based on two-dimensional vibrations of resonant nanowires. Nature Nanotech. 5, 641–645 (2010).

  18. 18.

    , & Ultimate limits to inertial mass sensing based upon nanoelectromechanical systems. J. Appl. Phys. 95, 2682–2689 (2004).

  19. 19.

    The Expanding Role of Mass Spectrometry in Biotechnology (MCC Press, 2003).

  20. 20.

    Towards Single-Molecule Nanomechanical Mass Spectrometry PhD thesis, California Insitute of Technology (2011).

  21. 21.

    , & Single molecule mass spectroscopy enabled by nanoelectromechnical systems. US patent 8,227,747 (2012).

  22. 22.

    , , & Enhanced functionality of cantilever based mass sensors using higher modes. Appl. Phys. Lett. 86, 233501 (2005).

  23. 23.

    , , & Mass and position determination of attached particles on cantilever based mass sensors. Rev. Sci. Instrum. 78, 103303 (2007).

  24. 24.

    , & Real-time particle mass spectrometry based on resonant micro strings. Sensors 10, 8092–8100 (2010).

  25. 25.

    Statistics of atomic frequency standards. Proc. IEEE 54, 221–230 (1966).

  26. 26.

    & Statistical Inference 2nd edn (Duxbury Press, 2001).

  27. 27.

    , & Efficient electrothermal actuation of multiple modes of high-frequency nanoelectromechanical resonators. Appl. Phys. Lett. 90, 093116 (2007).

  28. 28.

    et al. In-plane nanoelectromechanical resonators based on silicon nanowire piezoresistive detection. Nanotechnology 21, 165504 (2010).

  29. 29.

    Caltech/CEA-LETI Alliance for Nanosystems VLSI, 200 mm (second generation) Standard NEMS process: ‘CAL2′; available at .

  30. 30.

    , & in Sensors, 2008 IEE Conference 1135–1138 (IEEE, 2008).

  31. 31.

    , & Control of nucleation and growth of gold nanoparticles in AOT/Span80/isooctane mixed reverse micelles. J. Solid State Chem. 177, 3891–3895 (2004).

  32. 32.

    , , & Cluster size analysis of two-dimensional order in colloidal gold nanoparticle arrays. Langmuir 20, 9360–9365 (2004).

  33. 33.

    , , & Formation and adsorption of clusters of gold nanoparticles onto functionalized silica nanoparticle surfaces. Langmuir 14, 5396–5401 (1998).

  34. 34.

    The origin of macromolecule ionization by laser irradiation (Nobel Lecture). Angew. Chem. Int. Ed. 42, 3860–3870 (2003).

  35. 35.

    , , , & Production of IgM hexamers by normal and autoimmune B cells: implications for the physiologic role of hexameric IgM. J. Immunol. 161, 4091–4097 (1998).

  36. 36.

    , & Differential activation of human and guinea pig complement by pentameric and hexameric IgM. Eur. J. Immunol. 32, 1802–1810 (2002).

  37. 37.

    et al. Recombinant human hexamer-dominant IgM monoclonal antibody to ganglioside GM3 for treatment of melanoma. Clin. Cancer Res. 13, 2745–2750 (2007).

  38. 38.

    , , , & Amyloid-β oligomer specificity mediated by the IgM isotype—implications for a specific protective mechanism exerted by endogenous auto-antibodies. PLoS ONE 5, 13928 (2010).

  39. 39.

    & IgM—molecular requirements for its assembly and function. Immunol. Today 10, 118–128 (1989).

  40. 40.

    et al. Charge-reduced nano electrospray ionization combined with differential mobility analysis of peptides, proteins, glycoproteins, noncovalent protein complexes and viruses. J. Mass Spectrom. 36, 1038–1052 (2001).

  41. 41.

    et al. Electrospray ionization mass spectrometry and ion mobility analysis of the 20S proteasome complex. J. Am. Soc. Mass. Spectrom. 16, 998–1008 (2005).

Download references

Acknowledgements

The authors thank I. Bargatin, E. Myers, M. Shahgholi, I. Kozinsky, M. Matheny, J. Sader, P. Hung, E. Sage and R. Karabalin for helpful discussions, and C. Marcoux for assistance with device fabrication. The authors acknowledge the support and infrastructure provided by the Kavli Nanoscience Institute at Caltech, as well as support from the NIH (grant no. R01-GM085666-01A1Z), the NSF (MRI grant no. DBI-0821863), the Fondation pour la Recherche et l'Enseignement Superieur, an Institut Mérieux Research Grant, partial support from the Institut Carnot CEA-LETI and the Carnot-NEMS project, and a grant from the Partnership University Fund of the French Embassy to the USA. M.L.R. acknowledges support from an NIH Director's Pioneer Award and a Chaire d'Excellence (RTRA) from Fondation Nanosciences. S.H. and E.C. acknowledge partial support from EU CEA Eurotalent Fellowships.

Author information

Author notes

    • A. K. Naik

    Present address: Centre for Nano Science and Engineering, Indian Institute of Science, Bangalore, Karnataka, India

    • M. S. Hanay
    •  & S. Kelber

    These authors contributed equally to this work

Affiliations

  1. Kavli Nanoscience Institute and Departments of Physics, Applied Physics, and Bioengineering, California Institute of Technology, MC 149-33, Pasadena, California 91125 USA

    • M. S. Hanay
    • , S. Kelber
    • , A. K. Naik
    • , D. Chi
    • , S. Hentz
    • , E. C. Bullard
    • , E. Colinet
    •  & M. L. Roukes
  2. CEA, LETI, MINATEC Campus, 17 rue des Martyrs, 38054 Grenoble Cedex 9, France

    • S. Hentz
    • , E. Colinet
    •  & L. Duraffourg

Authors

  1. Search for M. S. Hanay in:

  2. Search for S. Kelber in:

  3. Search for A. K. Naik in:

  4. Search for D. Chi in:

  5. Search for S. Hentz in:

  6. Search for E. C. Bullard in:

  7. Search for E. Colinet in:

  8. Search for L. Duraffourg in:

  9. Search for M. L. Roukes in:

Contributions

M.L.R., A.K.N., M.S.H. and S.K. conceived and designed the experiments. M.S.H., S.K. and A.K.N. performed the experiments. M.S.H., S.K., A.K.N. and M.L.R. analysed the data. M.S.H., S.K., A.K.N., D.C., S.H., E.C.B., E.C., L.D. and M.L.R. contributed materials and analysis tools. M.S.H., S.K., M.L.R. and A.K.N. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to M. L. Roukes.

Supplementary information

PDF files

  1. 1.

    Supplementary information

    Supplementary information

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nnano.2012.119

Further reading