Single-molecule nanomechanical mass spectrometry


Nanoelectromechanical systems (NEMS) are enabling important emerging applications in diverse fields ranging from quantum measurement to biotechnology. In general, the smaller a device, the more susceptible are its physical properties to perturbation by external influences. This enhanced sensitivity of NEMS is opening a variety of unprecedented opportunities for applications such as mass spectrometry, which is now widely used for proteomics. Furthermore, to reliably detect the expression of low-level signals and to understand the fundamental biological processes, it is important to develop techniques capable of single cell or single-molecule analyses. In this work, the exceptional mass sensitivity of ultrahigh-frequency (UHF) NEMS resonators—derived from their miniscule masses, high frequencies, and high resonance quality factors—is used to demonstrate a new paradigm for mass spectrometry. Our approach enables the first real-time detection of individual protein molecules and nanoparticles as they adsorb on a sensitive NEMS detector. We use these to carry out an initial form of mass spectrometry based on discrete adsorption events.

NEMS-based mass spectrometry

Typically, mass spectrometers comprise three separate components that provide the critical functions of operation: analyte ionization, analyte separation and detection. Analyte species in the fluid phase are first ionized, and bare (uncollated) ions are produced using electrospray ionization (ESI)26,27. Second, ion separation is undertaken in vacuum based on the charge-to-mass (m/z) ratio of the analytes. Third, detection of clustered groups of these analytes with similar m/z values is carried out to determine the presence of a given species. Our new paradigm of NEMS–MS combines the latter two functions into one: the NEMS sensor is used as both mass analyzer and mass detector. This NEMS mass analyses/detector, in this first realization described here, is preceded by well-validated mass spectrometry components for analyte injection and delivery.

Schematically depicts our prototype experimental system, which introduces, transports and measures the masses of analytes. Protein ions or charged nanoparticles are produced and stripped of fluidic solvent during ESI. These bare ions traverse through a three-stage differentially pumped vacuum system and land onto the NEMS mass analyses/detector situated 2 m away from the ESI source. Two stages of hexapole ion optics28 driven at radio frequency (an RF-only hexapole) are used to guide the species to the NEMS with minimal m/z discrimination, as desired (see Supplementary Information). As the individual protein molecules and nanoparticles arrive and accrete onto the NEMS.

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Journal of Chromatography & Separation Techniques