MS/MS Data Improves Automated Determination of Molecular Formulas by Mass Spectrometry

In theory, the molecular formula of an unknown compound can be calculated from its exact molecular mass. However, even with highly accurate modern mass spectrometers with an accuracy of 1 ppm or lower, it is generally not possible to determine the molecular formula uniquely from measurements. Intensities of isotopic peaks are typically used as additional information to narrow down possible formulas associated with a mass spectrum (MS) peak, but this is not sufficient for larger compounds. Here, we introduce a method that takes information from fragment peak masses of the MS/MS into account to improve the reliability of formula determination. Matchvalues that reflect the consistency with MS isotope peaks and MS/MS fragment patterns are computed for candidate molecular formulas. We demonstrate that these matchvalues outperform methods based on isotope peak intensities alone. In test cases with medium sized organic molecules (< 1000 u) the true molecular formula achieves the highest matchvalues using the MS/MS data.

[1]  Florian Rasche,et al.  Towards de novo identification of metabolites by analyzing tandem mass spectra , 2008, ECCB.

[2]  Douglas B Kell,et al.  Metabolomic biomarkers: search, discovery and validation , 2007, Expert review of molecular diagnostics.

[3]  Ari Rantanen,et al.  FiD: a software for ab initio structural identification of product ions from tandem mass spectrometric data. , 2008, Rapid communications in mass spectrometry : RCM.

[4]  R. Friedman,et al.  Mass spectral metabonomics beyond elemental formula: chemical database querying by matching experimental with computational fragmentation spectra. , 2008, Analytical chemistry.

[5]  A. Kerber,et al.  Molecules in Silico: The Generation of Structural Formulae and Its Applications , 2004 .

[6]  H. Kubinyi CALCULATION OF ISOTOPE DISTRIBUTIONS IN MASS SPECTROMETRY. A TRIVIAL SOLUTION FOR A NON-TRIVIAL PROBLEM , 1991 .

[7]  A. Rockwood,et al.  Efficient calculation of accurate masses of isotopic peaks , 2006, Journal of the American Society for Mass Spectrometry.

[8]  Oliver Fiehn,et al.  Metabolomic database annotations via query of elemental compositions: Mass accuracy is insufficient even at less than 1 ppm , 2006, BMC Bioinformatics.

[9]  Zsuzsanna Lipták,et al.  SIRIUS: decomposing isotope patterns for metabolite identification , 2008, Bioinform..

[10]  D. Mathur,et al.  Computer-assisted determination of elemental composition of fragments in mass spectra , 1992 .

[11]  A. Marshall,et al.  High-resolution mass spectrometers. , 2008, Annual review of analytical chemistry.

[12]  Richard D. Smith,et al.  Rapid Calculation of Isotope Distributions , 1995 .

[13]  Automatische Erkennung von Isotopenpeakmustern in Massenspektren , 1985 .

[14]  H. Irth Continuous‐Flow Systems for Ligand Binding and Enzyme Inhibition Assays Based on Mass Spectrometry , 2007 .

[15]  J. Lederberg Rapid calculation of molecular formulas from mass values , 1972 .

[16]  Cristina Draghici,et al.  Molecular formula analysis by an MS/MS/MS technique to expedite dereplication of natural products. , 2007, Analytical chemistry.

[17]  Ernö Pretsch,et al.  A computer program for the computation of the molecular formula , 1989 .

[18]  N. E. Holden,et al.  Atomic weights of the elements 1983 , 1984 .

[19]  Silvia Heuerding,et al.  Simple tools for the computer-aided interpretation of mass spectra , 1993 .

[20]  J. Halket,et al.  Derivatization in Mass Spectrometry—2. Acylation , 2003, European journal of mass spectrometry.

[21]  J. Banoub,et al.  Mass Spectrometry, Review of the Basics: Electrospray, MALDI, and Commonly Used Mass Analyzers , 2009 .

[22]  Microcomputer program for determining elemental compositions of unknown organic compounds from low-resolution electron impact mass spectra , 1990 .

[23]  Oliver Fiehn,et al.  Seven Golden Rules for heuristic filtering of molecular formulas obtained by accurate mass spectrometry , 2007, BMC Bioinformatics.

[24]  E. Vuori,et al.  Isotopic pattern and accurate mass determination in urine drug screening by liquid chromatography/time-of-flight mass spectrometry. , 2006, Rapid communications in mass spectrometry : RCM.

[25]  Xuewu Zhang,et al.  Mass spectrometry-based "omics" technologies in cancer diagnostics. , 2007, Mass spectrometry reviews.

[26]  R. Cotter,et al.  Mass Spectrometry , 1992, Bio/Technology.

[27]  Emma L. Schymanski,et al.  Matching structures to mass spectra using fragmentation patterns: are the results as good as they look? , 2009, Analytical chemistry.

[28]  Werner Brack,et al.  How to confirm identified toxicants in effect-directed analysis , 2008, Analytical and bioanalytical chemistry.

[29]  J. Halket,et al.  Derivatization in Mass Spectrometry—8. Soft Ionization Mass Spectrometry of Small Molecules , 2006, European journal of mass spectrometry.

[30]  MOLECULES IN SILICO : POTENTIAL VERSUS KNOWN ORGANIC COMPOUNDS , 2005 .

[31]  Adalbert Kerber,et al.  CASE via MS: Ranking Structure Candidates by Mass Spectra , 2006 .

[32]  P. De Bièvre,et al.  Atomic weights of the elements. Review 2000 (IUPAC Technical Report) , 2009 .

[33]  Ross Ihaka,et al.  Gentleman R: R: A language for data analysis and graphics , 1996 .

[34]  J. K. Senior Partitions and Their Representative Graphs , 1951 .

[35]  Ernö Pretsch,et al.  Automated Compatibility Tests of the Molecular Formulas or Structures of Organic Compounds with Their Mass Spectra , 1999, J. Chem. Inf. Comput. Sci..

[36]  A. Rockwood,et al.  Ultrahigh-speed calculation of isotope distributions. , 1996, Analytical chemistry.

[37]  Aarni Tenhosaari Computer‐assisted composition analysis of unknown compounds by simultaneous analysis of the intensity ratios of isotope patterns of the molecular ion and daughter ions in low‐resolution mass spectra , 1988 .

[38]  S. Roussis,et al.  Reduction of chemical formulas from the isotopic peak distributions of high-resolution mass spectra. , 2003, Analytical chemistry.

[39]  K. Blom Enhanced selectivity in determining elemental composition: Concerted precise mass and isotope pattern moment analysis , 1988 .