A mass spectrometer for single-molecule protein sequencing

There is a rapidly expanding research effort to sequence proteins at the single-molecule level. Conventional protein sequencing relies on electrospray ionization mass spectrometry, but it is generally thought that alternative approaches are needed for single-molecule sequencing. This is not due to any problems inherent to mass spectrometry, which has single ion sensitivity and superb resolution. Rather, it is due to the chaotic and inefficient nature of electrospray ionization, resulting in only a small fraction of the sample molecules arriving at the mass analyzer. Here we report the development of a new mass spectrometry technique featuring a nanocapillary ion source capable of emitting single amino acid ions directly into high vacuum from aqueous solution, sidestepping the drawbacks of conventional electrospray. Emitted amino acids are focused by a set of ion optics and separated by a magnetic sector before striking an array of single ion detectors. We show that this instrument can detect and distinguish different amino acids with orders of magnitude greater efficiency than conventional electrospray. Adoption of these nanocapillary ion sources could open the door to single-molecule protein sequencing and single cell proteomics.