SGMS Meeting 2001: Plenary Lecture

Mass independent single molecule detectors for mass spectrometry

Daniel Gerber (1,3), Dominique Gritti (1), Yvan Gonin (1), Alexandre Netuschill (2), Frédéric Rossel (1), Dominique Schenker (1), Jean-Luc Vuilleumier (1), Damian Twerenbold (1,3)

1 Institut de Physique, Université Neuchâtel, Rue A.-L.Breguet 1, CH-2000 Neuchâtel, Switzerland
2 Institut de Microtechnique, Université Neuchâtel, Rue Jaquet-Droz 1, CH-2007 Neuchâtel, Switzerland
3 GenSpec SA, case postale 120, CH-2017 Boudry, Switzerland

We have introduced a novel type of molecule detector - cryogenic particle detectors - in time-of-flight mass spectrometry as a solution to the well known decrease in quantum efficiency for molecules with increasing mass. Cryodetectors have been developed in the last two decades for x-ray astrophysics and dark matter search in cosmology. This type of particle detector operates at temperatures below 1 Kelvin. Cryodetectors measure the energy deposition of a single molecule with a large signal-to-noise ratio. In a time-of-flight mass spectrometer, the kinetic energy of a molecule is the product of the molecule charge and the acceleration voltage, and hence does not depend on molecule mass. Because cryodetectors measure the energy deposition of a single molecule, they show a mass independent detection sensitivity, which is 100% on impact.

Cryodetector time-of-flight mass spectrometers are operated in the single molecule counting mode. Standard time-of-flight spectra are obtained by creating histograms of the arrival times of the individual molecule events. A cryodetector signal, however, carries additional information: the pulse height is proportional to the total energy deposited by the detected molecule. This allows to select specific events when creating the time-of-flight spectra, e.g. by taking only molecules with a specific charged state. In addition, this pulse height information of the single molecule events allows to reduce the molecular background, e.g. by discarding events which do not have the required total kinetic energy owing to fragmentation or loss of charge during acceleration or free flight.

We have perfomed a variety of experiments using different cryodetectors. By direct comparison of identical samples in the same MALDI-TOF mass spectrometer with both ionizing detectors and cryodetectors, we verified the strong exponential decrease of ionizing detectors with increasing mass. For IgG molecules with a mass of 135 kDa accelerated at 16 kV, we infer an increase of intrinsic detection efficiency of cryodetectors of at least 3 orders of magnitude as compared to ionizing detectors. We performed experiments with equimolar polydispersive PEG samples with mean masses between 1000 Da and 35000 Da and obtained mass spectra with identical peak integrals.