Electrospray ionization (ESI) and Matrix-Assisted Laser Desorption Ionization (MALDI) are both very powerful methods for the study of biomolecules which can be easily combined with an external-ion source differentially-pumped Fourier Transform Mass Spectrometer (FTMS). Using the unique "sidekick" continuous ion injection method into the trapped ion cell at the center of the superconducting magnet permits high sensitivity and high duty cycle for HPLC-ESI-FTMS. For both ESI-and MALDIFTMS the sensitivity, accuracy, MS/MS efficiency and analytical reliability increases significantly when an rf-shimmed "infinity" cell is used which avoids z-axis ion ejection by simulating an infinitely long rf field.

A novel microspray method developed by M. Mann et. al. at the EMBL is presented which in combination with ESI-FTMS requires only 1-2 microliters of solution to provide 20-30 minutes of stable ion signal for FTMS/MS and MSⁿ (n = 3, 4, ....) studies of biomolecules, especially peptides. Also, the use of quadrupolar excitation and axialization is demonstrated for improved resolution >10,000 for MALDI-FTMS, for sensitivity enhancements with ion remeasurement, and for improved MS/MS sensitivity and resolution.