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ModiFinder: Tandem Mass Spectral Alignment Enables Structural Modification Site Localization

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    ModiFinder: Tandem Mass Spectral Alignment Enables Structural Modification Site Localization
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    • Mohammad Reza Zare Shahneh
      Mohammad Reza Zare Shahneh
      Department of Computer Science and Engineering, University of California Riverside, 900 University Ave., Riverside, California 92521, United States
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    • Michael Strobel
      Michael Strobel
      Department of Computer Science and Engineering, University of California Riverside, 900 University Ave., Riverside, California 92521, United States
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    • Giovanni Andrea Vitale
      Giovanni Andrea Vitale
      Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, Auf der Morgenstelle 24, Tuebingen 72076, Germany
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    • Christian Geibel
      Christian Geibel
      Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, Auf der Morgenstelle 24, Tuebingen 72076, Germany
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      Orcidhttps://orcid.org/0009-0002-2044-9422
    • Yasin El Abiead
      Yasin El Abiead
      Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Dr., San Diego, California 92093, United States
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    • Neha Garg
      Neha Garg
      School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, 950 Atlantic Drive, Atlanta, Georgia 30332, United States
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    • Berenike Wagner
      Berenike Wagner
      Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, Auf der Morgenstelle 28, Tuebingen 72076, Germany
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    • Karl Forchhammer
      Karl Forchhammer
      Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, Auf der Morgenstelle 28, Tuebingen 72076, Germany
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    • Allegra Aron
      Allegra Aron
      Department of Chemistry and Biochemistry, University of Denver, 2101 East Wesley Ave, Denver, Colorado 80210, United States
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    • Vanessa V Phelan
      Vanessa V Phelan
      Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, 12850 E Montview Blvd, Aurora, Colorado 80045, United States
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      Orcidhttps://orcid.org/0000-0001-7156-9294
    • Daniel Petras
      Daniel Petras
      Department of Biochemistry, University of California Riverside, 900 University Ave., Riverside, California 92521, United States
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    • Mingxun Wang*
      Mingxun Wang
      Department of Computer Science and Engineering, University of California Riverside, 900 University Ave., Riverside, California 92521, United States
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0001-7647-6097
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    Journal of the American Society for Mass Spectrometry

    Cite this: J. Am. Soc. Mass Spectrom. 2024, 35, 11, 2564–2578
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jasms.4c00061
    Published June 3, 2024
    Copyright © 2024 American Society for Mass Spectrometry. Published by American Chemical Society. All rights reserved.
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    Abstract

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    Untargeted tandem mass spectrometry (MS/MS) has become a high-throughput method to measure small molecules in complex samples. One key goal is the transformation of these MS/MS spectra into chemical structures. Computational techniques such as MS/MS library search have enabled the reidentification of known compounds. Analog library search and molecular networking extend this identification to unknown compounds. While there have been advancements in metrics for the similarity of MS/MS spectra of structurally similar compounds, there is still a lack of automated methods to provide site specific information about structural modifications. Here we introduce ModiFinder which leverages the alignment of peaks in MS/MS spectra between structurally related known and unknown small molecules. Specifically, ModiFinder focuses on shifted MS/MS fragment peaks in the MS/MS alignment. These shifted peaks putatively represent substructures of the known molecule that contain the site of the modification. ModiFinder synthesizes this information together and scores the likelihood for each atom in the known molecule to be the modification site. We demonstrate in this manuscript how ModiFinder can effectively localize modifications which extends the capabilities of MS/MS analog searching and molecular networking to accelerate the discovery of novel compounds.

    Copyright © 2024 American Society for Mass Spectrometry. Published by American Chemical Society. All rights reserved.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jasms.4c00061.

    • Additional details, examples, and methods, including formulation of different evaluation metrics, and toy example illustrating the limitations of ModiFinder in scenarios characterized by imbalanced symmetry; detailed graphs of the performance of ModiFinder for different evaluatin methods and libraries; examples of ModiFinder’s functionality and the evaluation function demonstration for multiple examples and a preliminary model to predict the usefulness of ModiFinder; (39) graphical explanation of the CFM-ID method (PDF)

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    Cited By

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    This article is cited by 1 publications.

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    Journal of the American Society for Mass Spectrometry

    Cite this: J. Am. Soc. Mass Spectrom. 2024, 35, 11, 2564–2578
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jasms.4c00061
    Published June 3, 2024
    Copyright © 2024 American Society for Mass Spectrometry. Published by American Chemical Society. All rights reserved.
    Request reuse permissions

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