Multiple Ion Isolation Applications in FT-ICR MS:  Exact-Mass MS<i><sup>n</sup></i> Internal Calibration and Purification/Interrogation of Protein−Drug Complexes

Kruppa, Gary; Schnier, Paul D.; Tabei, Keiko; Orden, S. Van; Siegel, Marshall M.

doi:10.1021/ac020048q

Cited by 37 publications

(33 citation statements)

References 54 publications

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“…These include IRMPD in-trap cleanup ; MS n experiments (Little et al, 1994;Tonner & McMahon, 1997); IRMPD in an external ion reservoir (Hofstadler, Sannes-Lowery, & Griffey, 1999). Because IRMPD does not perturb the ion cloud high mass accuracy and resolution are readily obtained using this technique in combination with internal mass calibration (Dufresne, Wood, & Hendrickson, 1998;Hofstadler et al, 1998;Shi et al, 1999;Kruppa et al, 2002). Hofstadler et al (1998) utilized the observation that irradiation times for oligonucleotides are five to ten times shorter than for peptides and proteins and used proteins as internal standards for internal calibration of IRMPD spectra of oligonucleotides.…”

Section: Applicationsmentioning

confidence: 99%

Activation of large lons in FT‐ICR mass spectrometry

Laskin

Futrell

2004

Mass Spectrometry Reviews

177

146

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The advent of soft ionization techniques, notably electrospray and laser desorption ionization methods, has enabled the extension of mass spectrometric methods to large molecules and molecular complexes. This both greatly extends the applications of mass spectrometry and makes the activation and dissociation of complex ions an integral part of these applications. This review emphasizes the most promising methods for activation and dissociation of complex ions and presents this discussion in the context of general knowledge of reaction kinetics and dynamics largely established for small ions. We then introduce the characteristic differences associated with the higher number of internal degrees of freedom and high density of states associated with molecular complexity. This is reflected primarily in the kinetics of unimolecular dissociation of complex ions, particularly their slow decay and the higher energy content required to induce decomposition-the kinetic shift (KS). The longer trapping time of Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) significantly reduces the KS, which presents several advantages over other methods for the investigation of dissociation of complex molecules. After discussing general principles of reaction dynamics related to collisional activation of ions, we describe conventional ways to achieve single-and multiple-collision activation in FT-ICR MS. Sustained off-resonance irradiation (SORI)-the simplest and most robust means of introducing the multiple collision activation process-is discussed in greatest detail. Details of implementation of this technique, required control of experimental parameters, limitations, and examples of very successful application of SORI-CID are described. The advantages of high mass resolving power and the ability to carry out several stages of mass selection and activation intrinsic to FT-ICR MS are demonstrated in several examples. Photodissociation of ions from small molecules can be effected using IR or UV/vis lasers and generally requires tuning lasers to specific wavelengths and/ or utilizing high flux, multiphoton excitation to match energy levels in the ion. Photodissociation of complex ions is much easier to accomplish from the basic physics perspective. The quasi-continuum of vibrational states at room temperature makes it very easy to pump relatively large amounts of energy into complex ions and infrared multiphoton dissociation (IRMPD) is a powerful technique for characterizing large ions, particularly biologically relevant molecules. Since both SORI-CID and IRMPD are slow activation methods they have many common characteristics. They are also distinctly different because SORI-CID is intrinsically selective (only ions that have a cyclotron frequency close to the frequency of the excitation field are excited), whereas IRMPD is not (all ions that reside on the optical path of the laser are excited). There are advantages and disadvantages to each technique and in many applications they complement each other. In contrast wi...

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Section: Applicationsmentioning

confidence: 99%

Activation of large lons in FT‐ICR mass spectrometry

Laskin

Futrell

2004

Mass Spectrometry Reviews

177

146

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“…The TOF and Q 1 Q 2 Q 3 instruments are typically used in MS 2 (Premstaller & Huber, 2001;Yergey et al, 2002) but not in MS n experiments, whereas IT and FTICR are usually employed for that purpose (Kruppa et al, 2002;Wu et al, 2002). However, it must be emphasized that Q 1 Q 2 Q 3 instruments can produce medium-energy fragmentation (more structural information in the MS 2 spectra), whereas IT gives rise to low-energy fragmentation (it is often necessary to perform MS n analysis to obtain detailed structural information).…”

Section: Tandem Mass Spectrometrymentioning

confidence: 99%

Development of new methodologies for the mass spectrometry study of bioorganic macromolecules

Cristoni

Bernardi

2003

Mass Spectrometry Reviews

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I. Introduction 370 II. Techniques That Are Usually Employed in the Study of Bioorganic Macromolecules 371 A. Proteins and Peptides 371 B. Oligonucleotides 374 C. Oligosaccharides and Glycoconjugates 375 D. Various Complexes (DNA–Protein, Antigen–Antibody, Macromolecules–Metals) 377 III. Common Problems and Developments in the Analysis of Bioorganic Macromolecules by Mass Spectrometry 377 A. Ionization Source Problems and Developments 377 1. Sensitivity 377 2. Problems with Buffers 379 3. Multicharge Effect 381 B. Mass Analyzer Problems and Developments 381 1. Linear Dynamic Range 381 2. Tandem Mass Spectrometry 382 3. Sensitivity 382 4. Resolution 383 5. Mass Accuracy 383 IV. New Promising Technologies 384 A. Interfaces and Ionization Sources 384 1. Improvements in the Coupling of Liquid‐Phase Separation Systems to Mass Spectrometry 384 2. AP‐MALDI 384 3. Deprotonant Agents 385 4. Sonic Spray Ionization 388 5. APCI without Corona Discharge 391 B. Mass Analyzers 393 1. Linear Quadrupole Ion Trap 394 2. TOF Analyzers with New Detectors 395 3. Multiple Mass Analyzers 396 V. Software for Data Treatment 397 VI. Conclusions and Future Developments 399 Acknowledgments 400 References 400 In recent years, mass spectrometry has been increasingly used for the analysis of various macromolecules of biological, biomedical, and biochemical interest. This increase has been made possible by two key developments: the advent of electrospray ionization (ESI) and matrix‐assisted laser desorption ionization (MALDI) sources. The two new techniques produce a significant increase in mass range and in sensitivity that led to the development of new applications and of new analyzer designs, software, and robotics. This review, apart from the description of the status of mass spectrometry in the analysis of bioorganic macromolecules, is mainly devoted to the illustration of the more recent promising techniques and on their possible future evolution. © 2003 Wiley Periodicals, Inc., Mass Spec Rev 22:369–406, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mas.10062

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“…The application of mass spectrometry for studying noncovalent native interactions between proteins and ligands is also well established, and the optimization of experimental parameters to reflect solution composition (and minimize non-specific complexes) has been described [23][24][25][26][27][28][29][30][31][32][33][34][35]. On this basis, it was postulated that integration of DCL synthesis with a mass spectrometry based screen could fulfil the screening requirements alluded to above and so provide an alternative means for identifying the most effective combination of building blocks in a DCL with a given target.…”

mentioning

confidence: 99%

Direct screening of a dynamic combinatorial library using mass spectrometry

Poulsen

2006

J. Am. Soc. Mass Spectrom.

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A dynamic combinatorial library (DCL) screening approach is described that permits direct identification of the effective (from ineffective) combination of building blocks in the equilibrating DCL. The approach uses Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) together with sustained off-resonance irradiation collision activated dissociation (SORI-CAD) to detect noncovalent protein-DCL ligand complexes under native conditions. It was shown that in a single, rapid experiment one could concurrently identify all the ligands of interest from the DCL against a background of inactive DCL ligands while still in the presence of the target protein. This result has demonstrated that mass spectrometry may provide a fast preliminary screening approach to identify DCL candidates for later verification with more traditional but time-consuming analysis. The MS/MS enables DCL mixtures to be effectively deconvoluted without the need for either chromatography, synthesis of DCL sub-libraries, conversion of the DCL to a static library, or disruption of the protein-ligand complexes before analysis-all typically necessary for the current screening method for DCLs. ( -3]. The benefit of this additional dimension becomes readily evident when dynamic combinatorial libraries (DCLs) are prepared in the presence of a therapeutic target molecule. The reversible chemistry, together with the target acting as a template, permits self-screening owing to selection and amplification of the "best binders" by molecular recognition events between DCL constituents and the target. There are now multiple examples of ligand discovery from dynamic combinatorial libraries (DCLs) generated in the presence of protein targets [4 -20]. In principle, DCC has the potential to circumvent the need to individually synthesize, characterize, and screen each possible library constituent, however rapid detection of the enriched DCL product(s) still poses a serious analytical problem and is a critical limitation to DCC taking a prominent place in drug discovery [21]. The standard DCL screening approach must carry out the screening of identical DCLs twice-with and without the targetand then compare the equilibrium concentration profiles of all library ligands when generated in both the absence and presence (following disruption of the ligand-target complexes) of target protein [4, 7, 10, 14 -17]-the detection of ligand enrichment in the targeted DCL is the basis of identifying the "best binders". Unfortunately, this screening approach typically necessitates synthesis of individual library components to validate chromatographic (e.g., HPLC) or spectral (e.g., NMR) assignments; this is both labor-and time-intensive and has the effect of undermining the promoted advantages of DCC. The complexity of screening with this indirect method also increases with the size of the DCL owing to chromatographic and/or spectral overlap so that the preparation and screening of DCL sub-libraries becomes necessary for deconvolution of larger DCLs. For DCC to have ...

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Multiple Ion Isolation Applications in FT-ICR MS: Exact-Mass MSⁿ Internal Calibration and Purification/Interrogation of Protein−Drug Complexes

Cited by 37 publications

References 54 publications

Activation of large lons in FT‐ICR mass spectrometry

Activation of large lons in FT‐ICR mass spectrometry

Development of new methodologies for the mass spectrometry study of bioorganic macromolecules

Direct screening of a dynamic combinatorial library using mass spectrometry

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Multiple Ion Isolation Applications in FT-ICR MS: Exact-Mass MSn Internal Calibration and Purification/Interrogation of Protein−Drug Complexes

Cited by 37 publications

References 54 publications

Activation of large lons in FT‐ICR mass spectrometry

Activation of large lons in FT‐ICR mass spectrometry

Development of new methodologies for the mass spectrometry study of bioorganic macromolecules

Direct screening of a dynamic combinatorial library using mass spectrometry

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Product

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Multiple Ion Isolation Applications in FT-ICR MS: Exact-Mass MSⁿ Internal Calibration and Purification/Interrogation of Protein−Drug Complexes