Toward single-molecule nanomechanical mass spectrometry

Abstract

Mass spectrometry (MS) provides rapid and quantitative identification of protein species with relatively low sample consumption. Yet with the trend toward biological analysis at increasingly smaller scales, ultimately down to the volume of an individual cell, MS with few-to-single molecule sensitivity will be required. Nanoelectromechanical systems (NEMS) provide unparalleled mass sensitivity, which is now sufficient for the detection of individual molecular species in real time. Here we report the first demonstration of MS based on single-biological-molecule detection with NEMS. In our NEMS-MS system, nanoparticles and protein species are introduced by electrospray injection from fluid phase in ambient conditions into vacuum and subsequently delivered to the NEMS detector by hexapole ion optics. Precipitous frequency shifts, proportional to the mass, are recorded in real time as analytes adsorb, one-by-one, onto a phase-locked, ultrahigh frequency NEMS resonator. These first NEMS-MS spectra, obtained with modest mass sensitivity from only several hundred mass adsorption events, presage the future capabilities of this approach. We also outline the substantial improvements that are feasible in the near term, some of which are unique to NEMS-MS.