1 Welcome! Mass Spectrometry meets ChemInformatics Tobias Kind and Julie Leary UC Davis Course 3: Mass spectral and molecular database search Class website: CHE 241 - Spring 2008 - CRN 16583 Slides: http://fiehnlab.ucdavis.edu/staff/kind/Teaching/ PPT is hyperlinked – please change to Slide Show Mode
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1
Welcome!
Mass Spectrometry meets ChemInformaticsTobias Kind and Julie Leary
UC Davis
Course 3: Mass spectral and moleculardatabase search
Class website: CHE 241 - Spring 2008 - CRN 16583Slides: http://fiehnlab.ucdavis.edu/staff/kind/Teaching/PPT is hyperlinked – please change to Slide Show Mode
Important is data qualityAnnotation with CAS and Structure and FormulaLink to literature or publication usefulCurrently no large ESI,APPI,APCI libraries available (free or commercial)
PBM - Probability Based Matching (McLafferty & Stauffer) – since 1976Dot Product (Finnigan/INCOS) – since 1978Weighted Dot Product (Stein) – since 1993Mass Spectral Tree Search (Mistrik) – since 21st century
Source: Stein S.E. see notes
Au and Ar: are the abundances of peaks in the user and reference mass spectram: m/z values w: weighting term
The NIST MS Search program is the “gold standard” for EI spectral searchUsed for all types of unit resolution spectra MS/MS, APCI, ESI-MS spectra
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NIST MS Search program 2.0
Search everything:A) Library Search: Reverse, Normal, Similarity, Neutral LossB) Structure Similarity Search: find molecules similar to C) Formula Search: find C11H13N3O3SD) Constrained peak search: find peaks with m/z 122 and 188 and 266E) Name search: find Stuntman (maleic hydrazide)
Search Connections:Import/Export molecular structures: (msp, hpj, sdf)Interpret Structures (MSInterpreter.exe)Find substructures (expert algorithm)Import spectra from other programs (AMDIS, Chemstation, ChromaTOF)
(mainlib) Maleic hydrazide10 30 50 70 90 110
0
50
100
12
2641
55
68
82
92
112
NH
O
NH
O
[Download] – freely available (NIST05 MS Library is licensed ~ $1200)
Library search is always the first step during the identification process.Usually library search is not enough to assign unique isomer structures.
Mass spectra must be clean and background free before search.For LC-MS and GC-MS this requires peak picking and deconvolution.
Additional orthogonal information has to be used:
• restriction of compound space to certain species or material• use of isotope pattern information• use of retention index if derived from GC-MS data• use of retention – logp or logD correlations in case of LC-MS• additional fragmentation at different voltages (MSE)
Only certain mass spectra can be in-silico predicted (calculated)(peptides, lipids, carbohydrates) – this is not the rule for other molecules
CAS SciFinder• 33 million molecules and 60 million peptides/proteins• largest reaction DB (14 million reactions) and literature DB• substructure and similarity search of structures• a must for chemists and biochemists/biologists• no bulk download, no good Import/ Export, no Link outs
OCR – optical character recognitionDB – database(*) – and structures and other spectral data
PDFPDF
AB
Scientist ARuns MS
Publication on paperas bitmap graphic
OCR DB Curation DB Creation Sell DBScientist BNeeds DB
A BDB
Better:
Central and Open RepositoryElectronic Publishing in XML
Computerized Free or Paid Curation
Today:
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DB
Open data repository for mass spectra
Submit spectra before publication (ticket system) No loss of information (high resolution spectra)No truncated data (report five peaks only)No hamburger to cow algorithm needed (OCR)Fast and instant use with no restrictionsNew synergism for data interpretation Can still cost money (curation)Works in genomic sciences (GenBank)Commercial use may be possible Central and Open
There are different search types for mass spectral datasimilarity search, reverse search, neutral loss search, MS/MS search
There are large libraries for electron impact spectra (EI) from GC-MSThere are no large open/commercial libraries for spectra from LC-MS
For creation of mass spectral libraries a holistic approach is importantMass spectral trees can give further information (MSE or MSn)
There are different types of searching structuresExact search, similarity search, substructure search
Before you start a research project, create target lists of possible candidatesCollect mass spectra or structures in libraries with references
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Reading list (20 min)
Additional reading list for very diligent and interested pupils (30 min) (*)
An MS/MS Library on an Ion-Trap Instrument for Efficient Dereplication of Natural Products.Different Fragmentation Patterns for [M + H]+ and [M + Na]+ Ions
The History of the NIST/EPA/NIH Mass Spectral Database
(WO2006040622) DETERMINATION OF MOLECULAR STRUCTURES USING TANDEM MASS SPECTROMETRY [Link] [PDF]
Chemical derivatization and mass spectral libraries in metabolic profiling by GC/MS and LC/MS/MS
The critical evaluation of a comprehensive mass spectral library
Development and validation of a spectral library searching method for peptide identification from MS/MS
(*) Edison: “Two per cent is genius and 98 per cent is hard work”“Bah. Genius is not inspired. Inspiration is perspiration” [SOURCE]
1) Goto PubChem [LINK] or Chemspider [LINK] and perform the 3 different structure searches using benzene; report on the number of results(use the sketch function to draw benzene (6 ring with 3 aromatic bonds))
2) Download NIST MS Search [LINK] and perform the 3 different mass spectral searches on cocaine (download JAMP-DX from NIST [link])
3) Use Instant-JChem [LINK] from last course session and create a local demo database with PubChem data.Perform 3 different structure searches with benzene by double-clickingon the structure search field. Report number of results.
Additional task for proteomics candidates:4) Download the NIST peptide search [LINK] and perform a search on the given examples