title: Hydrogen Rearrangement Rules: Computational MS/MS Fragmentation and Structure Elucidation Using MS-FINDER Software.
abstract: Compound identification from accurate mass MS/MS spectra is a bottleneck for untargeted metabolomics. In this study, we propose nine rules of hydrogen rearrangement (HR) during bond cleavages in low-energy collision-induced dissociation (CID). These rules are based on the classic even-electron rule and cover heteroatoms and multistage fragmentation. We evaluated our HR rules by the statistics of MassBank MS/MS spectra in addition to enthalpy calculations, yielding three levels of computational MS/MS annotation: "resolved" (regular HR behavior following HR rules), "semiresolved" (irregular HR behavior), and "formula-assigned" (lacking structure assignment). With this nomenclature, 78.4% of a total of 18506 MS/MS fragment ions in the MassBank database and 84.8% of a total of 36370 MS/MS fragment ions in the GNPS database were (semi-) resolved by predicted bond cleavages. We also introduce the MS-FINDER software for structure elucidation. Molecular formulas of precursor ions are determined from accurate mass, isotope ratio, and product ion information. All isomer structures of the predicted formula are retrieved from metabolome databases, and MS/MS fragmentations are predicted in silico. The structures are ranked by a combined weighting score considering bond dissociation energies, mass accuracies, fragment linkages, and, most importantly, nine HR rules. The program was validated by its ability to correctly calculate molecular formulas with 98.0% accuracy for 5063 MassBank MS/MS records and to yield the correct structural isomer with 82.1% accuracy within the top-3 candidates. In a test with 936 manually identified spectra from an untargeted HILIC-QTOF MS data set of human plasma, formulas were correctly predicted in 90.4% of the cases, and the correct isomer structure was retrieved at 80.4% probability within the top-3 candidates, including for compounds that were absent in mass spectral libraries. The MS-FINDER software is freely available at http://prime.psc.riken.jp/ .
authors.affiliation: RIKEN Center for Sustainable Resource Science, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsugawa
authors.affiliation: Genome Center, University of California-Davis , Davis, California 95616, United States.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kind
authors.affiliation: RIKEN Center for Sustainable Resource Science, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nakabayashi
authors.affiliation: Reifycs Inc., Minato-ku, Tokyo 105-0003, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Yukihira
authors.affiliation: Department of Genetics, SOKENDAI (The Graduate University for Advanced Studies) , 1111 Yata, Mishima, Shizuoka 411-8540, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Tanaka
authors.affiliation: Genome Center, University of California-Davis , Davis, California 95616, United States.
authors.forename: Tomas
authors.initials: T
authors.lastname: Cajka
authors.affiliation: RIKEN Center for Sustainable Resource Science, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.|Graduate School of Pharmaceutical Sciences, Chiba University , 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Saito
authors.affiliation: Genome Center, University of California-Davis , Davis, California 95616, United States.|Biochemistry Department, King Abdulaziz University , Jeddah 21589, Saudi Arabia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.affiliation: RIKEN Center for Sustainable Resource Science, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.|Department of Genetics, SOKENDAI (The Graduate University for Advanced Studies) , 1111 Yata, Mishima, Shizuoka 411-8540, Japan.|National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Arita
mesh_terms: D015331:Cohort Studies; D018698:Glutamic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D005978:Glutathione / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D006859:Hydrogen / Q000737:chemistry*; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry; D015394:Molecular Structure; D010671:Phenylurea Compounds / Q000737:chemistry; D010767:Phosphorylcholine / Q000737:chemistry; D012984:Software; D053719:Tandem Mass Spectrometry
chemical_list: D010671:Phenylurea Compounds; D010767:Phosphorylcholine; D018698:Glutamic Acid; C028904:isoproturon; D006859:Hydrogen; D005978:Glutathione; D008239:Lysine