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bioRxiv · 10.1101/2024.10.18.619158

Abandoning the Quadrupole for Mass Spectrometry Fragmentation Analysis: Towards 1,000 Hz Speeds with 100% Ion Utilization Using High Resolution Ion Mobility Precursor Isolation

DeBord, D.·Rorrer, L.·Deng, L.·Strathmann, F.
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Abstract

In todays fast-evolving landscape of omics research, tandem mass spectrometry has become a cornerstone for uncovering the complexities of biological systems. Yet, despite its essential role, the technology remains bound by the inherent limitations of quadrupole filters, which throw away up to 99% of the useful ion signal and caps the speed at which fragmentation data can be generated. These deficiencies often force compromises in data depth and accuracy, hindering breakthroughs that tie genomics, proteomics, and metabolomics together. A new technology is poised to break through these performance barriers, unlocking unprecedented capabilities in precision, sensitivity and throughput. This step-change in how mass spectrometry fragmentation analysis is performed will reshape the future of scientific discovery, pushing the boundaries of whats possible. The solution is high resolution ion mobility (HRIM), which offers a means to quickly and efficiently isolate ions prior to fragmentation and detection by a high resolution mass spectrometer (HRMS) while also resolving challenging isomeric and isobaric compounds that lead to chimeric MS/MS spectra. HRIM isolates ions in time as a result of a high speed separation rather than acting as a filter that discards ion signal like the pervasive quadrupole mass analyzer, allowing higher sensitivity analysis to be achieved. Also, since HRIM eliminates the need to hop or sweep electronics control parameters, as is the case with a quadrupole, fragmentation spectral generation can occur at a much faster rate, upwards of 500 Hz. This whitepaper describes an IM/MS methodology first contemplated over twenty years ago and today being positioned as the fastest method for high resolution fragmentation analysis. Revisiting this concept using the latest generation ion mobility technology based on structures for lossless ion manipulation (SLIM), which is the only HRIM technology that delivers similar resolution and range of analysis as a quadrupole, realizes the full potential of this approach to deliver benefits in both speed and sensitivity for high performance MS/MS measurements. This new way of achieving ion fragmentation in complex samples is set to revolutionize the mass spectrometry space, starting in the growing field of proteomics where all researchers are seeking faster methods to achieve more comprehensive proteomic coverage. Due to the advantages of HRIM physics, we predict this will set the bar for high throughput -omics within the coming years and will eventually be as ubiquitous as the quadrupole is today.

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DeBord, D., Rorrer, L., Deng, L., Strathmann, F.. 2024-10-19. Abandoning the Quadrupole for Mass Spectrometry Fragmentation Analysis: Towards 1,000 Hz Speeds with 100% Ion Utilization Using High Resolution Ion Mobility Precursor Isolation. https://doi.org/10.1101/2024.10.18.619158

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