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Tandem FTMS of Large Biomolecules.

The application of MS to the analysis of large biomolecules has undergone explosive growth in the past 10 years. With the development of electrospray ionization (ESI) (1, 2) and matrix-assisted laser desorption/ionization (MALDI) (3), intact molecular ions of large molecules with molecular weights up to hundreds of megadaltons can now be formed and mass analyzed. These ionization methods have placed increasing demands on the performance of mass analyzers, challenging analytical chemists to develop new MS instrumentation and methods for obtaining molecular weight and structural information. MALDI has led to the resurgence of time-of-flight MS and new methods for increasing mass accuracy, sensitivity, and resolution. Similarly, mass analysis of multiply charged ions in the hundred-megadalton range, formed by ESI, has required the development of innovative detection methods. 
 
Tandem MS (MS/MS)—in which a precursor ion is mass selected from a mixture, dissociated or reacted, and the product ions are mass analyzed—has become a powerful method for analyzing complex mixtures of small molecules and solving “needle-in-the-haystack” problems. The dissociation and chemical reactivity of small ions have been extensively studied by a wide range of techniques, and a significant amount of information about energetics and mechanisms has been obtained (4). As a result, MS/MS has become a powerful analytical tool for characterizing trace quantities of compounds in complex mixtures. 
 
 
 
 
 
By comparison, the chemistry and structure of larger (>5 kDa) gas-phase ions is less well-known. However, significant advances have been made in recent years in instrumentation and structural characterization methods. These developments have made possible new applications of MS/MS for solving important problems in biochemistry and medicine, including obtaining sequence information, locating positions of post-translational modifications and binding sites, and identifying proteins found in cells. 
 
For MS/MS applications, ESI has an advantage because the technique forms multiply charged ions of large molecules with m/z values that are typically 500–2500. For molecules larger than ~3500 Da, multiple charging facilitates ion dissociation and the production of more structurally useful fragments than those obtained from the singly charged ions typically produced by MALDI. 
 
Various types of mass spectrometers are used for MS/MS experiments of ESI-generated ions. Of these instruments, Fourier transform MS (FTMS) has several powerful capabilities that make it well-suited to this application (5, 6). These capabilities include ultrahigh mass resolution (>105 at m/z 1000); ion remeasurement; multichannel detection over a wide mass range; long ion storage times; and extensive MSn capabilities, including two-dimensional methods for simultaneously recording MS/MS and MSn spectra (7). The combination of ESI with FTMS is becoming one of the most powerful methods for the structural analysis of large biomolecules. This Report covers selected topics that illustrate the type of information that is currently obtainable by ESI-FTMS. More comprehensive reviews on both ESI (1, 2) and FTMS (5–7) are available.