The Role of Ion Mobility Spectrometry - Mass Spectrometry (IMS-MS) in the Pharmaceutical Industry

Ion mobility spectrometry coupled with mass spectrometry (IMS-MS) is a powerful hyphenated technology widely used for pharmaceutical applications that benefit from increased measurement sensitivity, peak capacity, and scope of molecular data.

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As a stand-alone technique, IMS is used for rapid molecular separations in the gas phase based on the size, shape, charge, and mass of ions. Coupling with MS (IMS-MS) adds an extra dimension of resolution by enabling the separation and structural characterization of similar species for accurate identification and quantification of analytes.

Interest in IMS-MS has grown considerably over the last two decades and the number of systems available on the commercial market is expanding as ion mobility increasingly becomes an integral part of high-end mass spectrometers.

The more advanced, popular and available IMS-MS systems become, the more these instruments are being routinely applied in numerous different areas for the study of large molecules and complexes, as well as small molecule research.

The important transformations that the diversifying IMS-MS technique is making to the field of biomedical research will be a hot topic at Pittcon 2020 in Chicago IL and will be the central focus of the 31st James L Waters Symposium.

Combining IMS with TOF-MS systems

Since IMS separation occurs on the millisecond timescale, combining it with time-of-flight (TOF) MS systems is particularly popular because the unprecedented data acquisition rate of TOF-MS allows thousands of MS spectra to be generated in this millisecond separation timeframe.

In a session entitled “Ion Mobility Spectrometry-Mass Spectrometry (IMS-MS),” Kevin Giles will present his talk “The Development of Travelling Wave Ion Mobility Separation.” Giles will discuss the more recent uptake of IM-MS in the context of the increasing availability of high-performance instruments. Giles will describe the development of the technology behind the Synapt HDMS (quadrupole/IM/time-of-flight [TOF]MS) launched by Waters in 2006 and the traveling wave (TW)-based mobility separator that it features.

The use of IMS-MS in the pharmaceutical industry for protein characterization

In the pharmaceutical industry, accurate characterization of protein structure is crucial to understanding protein function and in facilitating the design of effective therapeutics. IMS separates ions based on their differential mobility through a drift-tube containing buffer gas. The differing mobility depends on an ion’s characteristic collision cross-section (CSS), which is greater in the case of larger ions that experience more collisions and take longer to cross the drift tube than smaller ions. One problem with IMS is that CCS data can only be averaged because gaseous ions collide with the buffer gas in various different orientations. However, interfacing with MS overcomes this problem and enables accurate characterization of proteins structures and complexes (Ashcroft et al 2013).

Coupling with liquid chromatography

The fast measurements IMS–MS provides means it couples well with other front-end analytical separations, such as liquid chromatography and capillary electrophoresis (Robinson and Jiang 2013).

Capillary LC-MS is now broadly applied in various areas of analytical application, particularly when high dynamic range characterization of complex mixtures is desired. The high-speed of IMS, as well as its robust nature, easy coupling with MS and the provision of additional structural information has meant IMS separations have gained increasing interest. However, one limitation is the resolving power that can be achieved.

This year at Pittcon Richard Smith will give a talk on “Ion Mobility Separations with Mass Spectrometry based upon Structures for Lossless Ion Manipulations (SLIM),” Smith will outline new approaches using traveling wave (TW) based Structures for Lossless Ion Manipulations (SLIM) and their application in conjunction with MS. He will describe the broad flexibility for manipulating ions in SLIM, and the multi-pass separations this provides to achieve much higher IM resolution and problematic separations than were previously possible.

Characterizing Native And Non-Native Protein Structures

In the context of native mass spectrometry, IMS-MS can be used for detailed structural analysis of diverse protein systems, providing information on the stoichiometry, composition, topology, and cross-section of large and heterogeneous protein complexes and their composite subunits, including protein systems as challenging as amyloid aggregates and membrane proteins (Sharon and Ben-Nissan 2018; Heck et al 2010).

By providing insights into the conformational dynamics of protein assemblies, IMS-MS offers a unique means of characterizing flexibility and folding mechanisms (Eyers et al 2014), one of the most challenging areas in biochemistry. Previously, experimental characterization of protein folding has been impeded by the tendency of proteins to melt.

A talk by David Clemmer “Mass-spectrometry based Strategies for Characterizing Native and Non-native Protein Structures” at Pittcon 2020 will present new data obtained from an IMS-MS analysis of simple proteins that were electrosprayed from a temperature-controlled source.

Electrospray ionization (ESI) has been one of the most commonly used ion sources in IMS–MS and MS applications since it was first discovered and applied to biological molecules in research conducted by Nobel laureate John Fenn and colleagues (Robinson and Jiang 2013)

Clemmer will describe how the data obtained enable detailed thermodynamic information to be extracted about different structures and the stabilities of new states involved in folding and unfolding events, that could help guide theoretical efforts to model folding processes.

David Russel will also discuss native ion mobility-mass spectrometry (IM-MS) as an important characterization technique for structural biology and the performance aspects of  IM-MS instruments that currently fall short of those needed for studying intact macromolecule complexes. Russell and colleagues plan to build and validate an integrated workflow for structural characterization of protein:protein; membrane protein:lipid; and protein:RNA complexes that are vital for a multitude of cellular and organismal processes. A major part of this effort is focused on developing next-generation IM-MS instruments with increased resolving power in both mobility and mass domains for studies of model protein complexes as well as membrane protein complexes.

Find out more at Pittcon 2020

The research and technologies highlighted here will be covered in more detail in the symposia, oral presentations and short courses at Pittcon 2020. Check out the Pittcon 2020 guide to learn more about these talks, symposia and courses and their presenters.

Numerous market-leading companies, including Agilent, Waters Corporation and Bruker will also be present at Pittcon 2020 to discuss the latest additions to their capabilities and additional analytical requirements.

References

1. Ashcroft A, et al. Advances in ion mobility spectrometry-mass spectrometry reveal key insights into amyloid assembly. Biochim Biophys Acta. 2013;1834(6):1257–1268. doi:10.1016/j.bbapap.2012.10.002

2. Robinson A and Jiang W. Ion Mobility-Mass Spectrometry. Encyclopedia of Analytical Chemistry 2013. DOI: 10.1002/9780470027318.a9292

3. Sharon M and Ben-Nissan G. The application of ion-mobility mass spectrometry for structure/function investigation of protein complexes. Current Opinion in Chemical Biology 2018;42: 25–33 https://doi.org/10.1016/j.cbpa.2017.10.026

4. Heck A, et al. Ion mobility mass spectrometry of proteins and protein assemblies. Chemical Society Reviews 39(5):1633-55 DOI: 10.1039/b914002f

5. Gray, C. et al. The power of ion mobility-mass spectrometry for structural characterization and the study of conformational dynamics. Nature Chem 2014;6: 281–294 doi:10.1038/nchem.1889

About Pittcon

Pittcon® is a registered trademark of The Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy, a Pennsylvania non-profit organization. Co-sponsored by the Spectroscopy Society of Pittsburgh and the Society for Analytical Chemists of Pittsburgh, Pittcon is the premier annual conference and exposition on laboratory science.

Proceeds from Pittcon fund science education and outreach at all levels, kindergarten through adult. Pittcon donates more than a million dollars a year to provide financial and administrative support for various science outreach activities including science equipment grants, research grants, scholarships and internships for students, awards to teachers and professors, and grants to public science centers, libraries and museums.

Visit pittcon.org for more information.


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Last updated: Feb 1, 2024 at 7:16 AM

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