Enhanced Charge-Sensitive Amplifier Performance Leads to Substantially Reduced CD-MS Measurement Times for Charge State Resolution.

In charge detection mass spectrometry (CD-MS) ions are trapped in an electrostatic linear ion trap (ELIT) where they oscillate back and forth through a conducting cylinder. The oscillating ions induce a periodic charge separation that is detected by a charge sensitive amplifier (CSA) connected to the cylinder. The resulting time domain signal is analyzed using short-time Fourier transforms to give the mass-to-charge ratio and charge for each ion, which are then multiplied to give the mass. For ions to be assigned to the correct integer charge states with a low error rate, the charge should be measured with a precision of <0.2 e (elementary charges). Electrical noise reduces the precision of the charge measurement. However, the effect of the noise can be ameliorated by signal averaging, and the measurement time can, in principle, be increased to achieve a precision of <0.2 e. Previously, through optimized ELIT design and improvements to the CSA, the measurement time (with a cryogenically cooled input JFET) required to achieve a charge precision of <0.2 e was reduced by a factor of 2, from 3 s to 1.5 s. In this study, further improvements in JFET selection, capacitance matching, and cryogenic cooling has allowed us to further reduce the electrical noise so that the target precision of <0.2 e can now be achieved for mAb MSQC4 in 600-700 ms with the input JFET cryogenically cooled, and in 900-1000 ms with the input JFET at room temperature. This performance upgrade cuts the overall time for high-resolution charge measurements by more than another factor of 2. For a measurement time of 100 ms, the charge RMSD is 0.51 e with cryogenic cooling. The results presented here further cements CD-MS with an ELIT as the fastest and most accurate approach to single ion MS measurements.