SPECIAL FEATURE: INTRODUCTORY PERSPECTIVE Mass spectrometry across the sciences Fred W. McLafferty* Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853 ass is a fundamental yet Although valued for its Ϸ90% hydrocar- air can desorb molecules directly for easily understood character- bon content, its compounds containing MS, such as insecticides on fruit or istic of a chemical species. the elements N, O, and S are a serious drugs on currency (11). For a tissue For many analytical prob- problem for poisoned catalysts, corro- sample, this can provide the spatial dis- Mlems, mass is also highly specific. J. J. sion, pollution, etc. High resolving- tribution of a specific drug or metabo- Thomson’s 1912 mass spectrum of neon power (Ͼ400,000) MS has identified lite. Matrix-assisted laser desorption/ Ͼ showed isotopes of masses 20 and 22 in 60,000 isotopic compositions ionization (MALDI) is used to map 12 1 14 16 32 a 10:1 ratio, explaining its apparently CcHh Nn Oo Ss based on the packing- specific proteins in brain tissue and hu- anomalous atomic weight of 20.2 (1). fraction differences (variation from unit man breast carcinoma, with four trun- Mass spectrometry (MS) then became mass) of these five isotopes. Using the cated forms of the ␤-amyloid protein important for such fundamental data of high sensitivity of MS, unexpected hy- also found directly in Alzheimer’s elements and for isotopic analysis, such drocarbons have been reported in extra- plaques (12). MALDI MS imaging has as 235U/238U in the nuclear weapons pro- terrestrial samples (7). However, a new been applied to human biopsies in col- gram. Also critical in World War II, MS two-step laser technique applicable to laboration with pathologists in studies replaced laborious analytical distillations captured 81P/Wild 2 cometary particles of light hydrocarbon gases, such as buta- shows that impact heating can produce aimed at developing improved diagnoses diene feedstocks for the synthetic rubber artifactual organic compounds along and treatment efficacy assessments, vital program. Gaseous ions are required for particle capture tracks in aerogel. issues in the growing area of personal- mass separation; ionization of a mole- Application of this technique to other ized medicine. Such analysis and characterization of cule such as butane, C4H10, causes bond carbonaceous samples suggests that the dissociation into many fragments (CH3, unexpected fullerenes found recently peptides and proteins (‘‘proteomics’’) C2H5,C3H7, etc.), so that their masses can be artifacts of laser heating. (13) has been the fastest expanding and relative abundances provide multi- Details of the transition from con- area, by far, that has resulted from ple characteristics for both specificity densed phase to gas phase can be methods for introducing nonvolatiles and quantitation (2). Furthermore, ion inferred from gaseous clusters by ob- into the mass spectrometer (4, 5). A detectors give unusual sensitivity and serving the change in their MS spectra critical review of advancing MS capabili- recording speed. Complex mixture anal- with increase in the number of their ties for large-scale analyses of the pro- ysis became routine by coupling MS on- monomer or solvent units; a sufficiently tein complement of cells, tissues, and line to gas and liquid chromatography, high number of units can simulate bulk body fluids comes from two leading re- with computer automation providing far properties (8). The hydrated electron, a search laboratories. A strong case is more information far faster. Additional powerful reductant basic to fields from made that MS proteomics has now molecular specificity became possible radiation chemistry to biology, is studied reached a new level of accuracy and ef- with ‘‘MS/MS,’’ in which additional mass in electrosprayed clusters of multivalent ficiency using far more sophisticated spectra are obtained from the mole- metal ions with an increasing number of instrumentation with online liquid chro- cule’s fragment ions or from the individ- H2O molecules; the electron capture matographic separation of complex mix- ual molecular ions of a mixture mass energy can be measured by the extent of tures, subsecond spectral measurement spectrum (3). H2O loss. Some metal ions in H2O clus- of unusual mass accuracy (parts per mil- In the last two decades, these molecu- ters suffer charge reduction, whereas lion) and resolving power (Ͼ105), and lar MS capabilities have been dramati- others show different types of electron efficient computer automation for re- cally extended by the development of and ion solvation. Bulk W O catalyzes n 3n duction and interpretation of the results. methods such as laser desorption (4) the oxidation of propene to propene Protein characterization by ESI/MS and electrospray ionization (ESI) (5) to oxide and CO to CO2 (9). In this reac- ϩ has been extended even to megadalton ionize and introduce nonvolatile mole- tion, gaseous WnO3n species of selected cules into the mass spectrometer. It be- n values exhibit enhanced activity and protein complexes (14). Despite its size came possible to obtain mass spectra of selectivity, indicating a radical oxygen and 13 subunits, ESI of the 800-kDa proteins, DNA/RNA, carbohydrates, lip- center (W-O•) mechanism. Related MS eukaryotic translation factor eIF3 yields ids, polymers, etc., with their increased studies investigate gaseous ion reactions intact molecular ions. Mass spectra of data complexity offset by dramatic in- to activate methane for conversion to its dissociation products show that it strument improvements in resolving more useful products such as methanol contains three relatively stable modules, power and mass accuracy. This has led (10). Reaction mechanisms inferred whose interactions are defined by 27 to diverse MS methodology for research from C(H,D)4 isotope effects differ subcomplexes. For many other proteins, and analysis, with unique capabilities of widely with variation of transition metal however, the native solution conforma- specificity, sensitivity, speed, sampling, reactants and their ligands, suggesting tion is not retained in the gas phase and automated computer data acquisition/ strategies for the further improvement (15). A variety of recent evidence shows reduction. of technical processes. that folding, unfolding, and refolding of This special issue attempts to illus- Recent MS techniques directly image trate the breadth and uniqueness of ap- biomedically-important molecules in tis- plications of molecular MS to a variety sue samples, illustrating the complemen- Author contributions: F.W.M. analyzed data and wrote the of scientific fields with current examples. tarity of ESI and laser desorption for paper. The specificity of MS is shown dramati- transferring a wide variety of molecules The author declares no conflict of interest. cally by the characterization of petro- into the mass spectrometer. A solvent *E-mail: [email protected]. leum, a notoriously complex mixture (6). electrosprayed onto an object in open © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0800784105 PNAS Early Edition ͉ 1of2 Downloaded by guest on October 1, 2021 protein tertiary structure can occur in daily use worldwide for identification so forth. Hopefully, the illustrations the 10Ϫ12 to 102 s after electrospray in- and analysis of a wide range of mole- here will suggest further novel ap- troduction into the mass spectrometer. cules, including flavors, natural prod- plications in other scientific fields Where experimentally desirable, control ucts, pollutants, drugs, metabolites, represented by the uniquely broad of specific steps can make possible and those in chemical process streams. readership of PNAS. either retention or appropriate modifica- MS specificity is ideal for efficiently tion of conformation during introduc- probing the molecular complexity ACKNOWLEDGMENTS.The authors of references tion into the mass spectrometer. found in many fields including agricul- 6–15 offered helpful suggestions. Generous fi- nancial support was supplied by the National In- This sampling represents only a tiny ture, atmospheric chemistry, biomedi- stitute of General Medicine, the National Insti- fraction of the mass spectrometers in cine, food, forensics, geochemistry, and tutes of Health, Grant GM16609. 1. Aston FW (1922) Isotopes (Arnold, London), pp 33–35. molecules: Mini-review and examination of pulsed metabolites in tissues. Proc Natl Acad Sci USA 2. McLafferty FW (1966) Interpretation of Mass Spectra heating effects. Proc Natl Acad Sci USA 105:●●●. 105:●●●. (Benjamin, New York), p 1. 8. Donald WA, Leib RD, O’Brien JT, Holm AIS, Williams ER 12. Seeley EH, Caprioli RM (2008) Molecular imaging of 3. McLafferty FW, ed (1983) Tandem Mass Spectrometry (2008) Nanocalorimetry in mass spectrometry: A route proteins in tissues by mass spectrometry. Proc Natl Acad (Wiley, New York). to understanding ion and electron solvation. Proc Natl Sci USA 105:●●●. 4. Karas M, Bachmann D, Bahr U, Hillenkamp F (1987) Acad Sci USA 105:●●●. 13. Mann M, Kelleher NL (2008) Precision proteomics: The Matrix-assisted ultraviolet laser desorption of non- 9. Johnson GE, Tyo EC, Castleman AW, Jr (2008) Cluster case for high resolution and high mass accuracy. Proc volatile compounds. Int J Mass Spectrom 78:53–68. reactivity experiments: Employing mass spectrome- Natl Acad Sci USA 105:●●●. 5. Fenn JB, Mann M, Meng CK, Wong SF, Whitehouse CM try to investigate the molecular level details of cat- 14.