Coupling Drift Tube Ion Mobility Measurements with Charge Detection Mass Spectrometry for the Analysis of Virus-like Particles and Other Megadalton-Sized Ions

The coupling of ion mobility (IM) measurements and mass spectrometry (IM-MS) has provided valuable structural information for gas phase ions and helped to resolve complex mixtures. However, the mass range of conventional MS is limited by the loss of charge state resolution, and this has essentially precluded the application of IM-MS methods to large particles and complexes with masses in the megadalton regime (and beyond) as well as to heterogeneous and complex mixtures in general. Single particle measurements can overcome the limitations of conventional MS and enable mass measurements for heterogeneous and high mass samples. In the work presented below, we describe the coupling of IM measurements with charge detection mass spectrometry (CD-MS). In CD-MS, ions oscillate back and forth through a detection cylinder embedded in an electrostatic linear ion trap. Charge and <i>m</i>/<i>z</i> are simultaneously measured for each ion and then multiplied to give the mass. The combined IM-CD-MS instrument developed here employs a linear drift tube that operates at subambient pressures. Its performance is illustrated by single ion measurements on a small protein complex (l-glutamate dehydrogenase) and a range of VLPs with masses up to 25 MDa (bacteriophage Qβ VLPs, hepatitis B virus VLPs, and Norovirus VLPs). The results demonstrate the benefit of complementary mass and mobility measurements for the analysis of high mass ions.