Shahneh Mohammad Reza Zare, Strobel Michael, Vitale Giovanni Andrea, Geibel Christian, Abiead Yasin El, Garg Neha, Wagner Berenike, Forchhammer Karl, Aron Allegra, Phelan Vanessa V, Petras Daniel, Wang Mingxun
Department of Computer Science and Engineering, University of California Riverside, 900 University Ave., Riverside, California 92521, United States.
Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, Auf der Morgenstelle 24, Tuebingen 72076, Germany.
J Am Soc Mass Spectrom. 2024 Nov 6;35(11):2564-2578. doi: 10.1021/jasms.4c00061. Epub 2024 Jun 3.
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.
非靶向串联质谱（MS/MS）已成为一种用于测量复杂样品中小分子的高通量方法。一个关键目标是将这些MS/MS光谱转化为化学结构。诸如MS/MS库搜索等计算技术已能够重新鉴定已知化合物。类似物库搜索和分子网络将这种鉴定扩展到未知化合物。虽然在结构相似化合物的MS/MS光谱相似性指标方面已有进展，但仍缺乏提供有关结构修饰的位点特异性信息的自动化方法。在此，我们介绍ModiFinder，它利用结构相关的已知和未知小分子的MS/MS光谱中的峰对齐。具体而言，ModiFinder关注MS/MS对齐中发生位移的MS/MS碎片峰。这些位移峰推测代表已知分子中包含修饰位点的子结构。ModiFinder将这些信息综合起来，并对已知分子中每个原子成为修饰位点的可能性进行评分。我们在本手稿中展示了ModiFinder如何有效地定位修饰，这扩展了MS/MS类似物搜索和分子网络的能力，以加速新型化合物的发现。
