There are several flavors of IM, including drift tube (DTIMS), travelling wave (TWIMS), trapped (TIMS) and field asymmetric waveform (FAIMS), which are described in detail elsewhere, however they all act to separate ions based on their size and shape. For some molecules, including proteins, IM measurements can even be turned into low resolution structural information in the form of collision cross section (CCS) values, which can then be matched to crystals or structures obtained from molecular dynamics experiments. These IM methods have been successfully integrated into a range of MS instrumentation with exciting results, however due to their synergistic timescales the majority of commercial instruments pair IM with time-of-flight (ToF) analyzers. To date, attempts have been made to combine linear IM with TDMS experiments on ToF instruments both pre-and post-activation, and these methods have shown great benefits in distinguishing backbone isomerization and sequence variation, improving sequence coverage, and mapping regions of unfolding or structural variation. Whilst these are impressive achievements, it could be argued that since the matching of fragmentation patterns to single conformers occurs during the post-collection processing rather than the actual MS workflow, attempts to match structural elements directly to conformers could be subject to interference or cross-contamination, introducing a source of unreliability. More recently, new instruments with enhanced IM resolution and tandem IM capabilities have been developed, which can potentially overcome this reliance on processing by enabling single conformer isolation in-instrument. To date, these more advanced IM instruments have been combined with collision, electron and surface-based activation techniques, however, the focus of these studies has been either using dissociation methods pre-IM and using the IM resolution gains to improve sequence coverage, or performing single conformer isolation on denatured structures purely for the purpose of distinguishing isomers. As such, the benefits of these enhanced IM capabilities, particularly the isolation of single conformers, in interpreting native protein fragmentation patterns in the context of protein structures remain unexplored.