Analyzing Biomolecular Interactions by Mass Spectrometry

Jeroen Kool focused on the integration of chemical and biochemical detection after separation methodologies during his PhD study at the VU University Amsterdam. Following his PhD, he was responsible for target evaluation, hit screening and identification, and lead optimization processes at Kiadis Pharma. He continued his academic career in 2005 as a postdoc in the Biomolecular Mass Spectrometry group in Utrecht working on proteomics and biomarker discovery. From 2007 to present, he is responsible for the research line Bioanalytical Screening Methodologies at the VU University Amsterdam with a particular focus on hyphenated analytical techniques combining mass spectrometry and chromatography with novel bioassay techniques for bioactive mixture analysis. He published over 50 peer reviewed articles and one book chapter. Wilfried M.A. Niessen studied chemistry at the VU University Amsterdam. After his PhD, he worked for 9 years as an analytical chemist within the Leiden/ Amsterdam Center for Drug Research at Leiden University. After leaving the university in 1996, he started the company hyphen MassSpec, providing independent consultancy and training in the field of analytical mass spectrometry. In parallel to this, he was extraordinary professor in bioanalytical mass spectrometry at the Faculty of Science of the VU University Amsterdam between 2002 and 2014. There, he was involved in high-resolution screening and the role of MS therein. His main research interests involve principles, instrumentation and applications of liquid chromatography-mass spectrometry as well as interpretation of small-molecule MS-MS mass spectra. He is (co)author of more than 200 peer reviewed publications in the field of LC-MS and more than 40 book chapters. Wilfried Niessen authored and edited five books, and was guest editor on several special journal issues.

• List of Contributors XIIIPreface XVIIAbbreviations XIX1 Introduction to Mass Spectrometry, a Tutorial 1Wilfried M.A. Niessen and David Falck1.1 Introduction 11.2 Figures of Merit 11.2.1 Introduction 11.2.2 Resolution 21.2.3 Mass Accuracy 41.2.4 General Data Acquisition in MS 51.3 Analyte Ionization 61.3.1 Introduction 61.3.2 Electrospray Ionization 81.3.3 Matrix-Assisted Laser Desorption Ionization 101.3.4 Other Ionization Methods 101.3.5 Solvent and Sample Compatibility Issues 111.4 Mass Analyzer Building Blocks 121.4.1 Introduction 121.4.2 Quadrupole Mass Analyzer 131.4.3 Ion-Trap Mass Analyzer 131.4.4 Time-of-Flight Mass Analyzer 151.4.5 Fourier Transform Ion Cyclotron Resonance Mass Spectrometer 161.4.6 Orbitrap Mass Analyzer 171.4.7 Ion Detection 181.5 Tandem Mass Spectrometry 181.5.1 Introduction: “Tandem-in-Time” and “Tandem-in-Space” 181.5.2 Ion Dissociation Techniques 201.5.3 Tandem Quadrupole MS–MS Instruments 211.5.4 Ion-Trap MSn Instruments 231.5.5 Tandem TOF (TOF–TOF) Instruments 231.5.6 Hybrid Instruments (Q–TOF, Q–LIT, IT–TOF) 241.5.7 MS–MS and MSn in FT-ICR-MS 261.5.8 Orbitrap-Based Hybrid Systems 271.5.9 Ion-Mobility Spectrometry–Mass Spectrometry 281.6 Data Interpretation and Analytical Strategies 301.6.1 Data Acquisition in MS Revisited 301.6.2 Quantitative Bioanalysis and Residue Analysis 311.6.3 Identification of Small-Molecule “Known Unknowns” 321.6.4 Identification of Drug Metabolites 331.6.5 Protein Molecular Weight Determination 371.6.6 Peptide Fragmentation and Sequencing 381.6.7 General Proteomics Strategies: Top-Down, Middle-Down, Bottom-Up 391.7 Conclusion and Perspectives 43References 43Part I Direct MS Based Affinity Techniques 552 Studying Protein–Protein Interactions by Combining Native Mass Spectrometry and Chemical Cross-Linking 57Michal Sharon and Andrea Sinz2.1 Introduction 572.2 Protein Analysis by Mass Spectrometry 582.3 Native MS 592.3.1 Instrumentation for High-mass ion Detection 602.3.2 Defining the Exact Mass of the Composing Subunits 602.3.3 Analyzing the Intact Complex 612.4 Chemical Cross-linking MS 642.4.1 Types of Cross-linkers 642.4.2 MS/MS Cleavable Cross-linkers 662.4.3 Data Analysis 682.5 Value of Combining NativeMS with Chemical Cross-linkingMS 682.6 Regulating the Giant 692.7 Capturing Transient Interactions 702.8 An Integrative Approach for Obtaining Low-Resolution Structures of Native Protein Complexes 722.9 Future Directions 73References 743 Native Mass Spectrometry Approaches Using Ion Mobility-Mass Spectrometry 81Frederik Lermyte, Esther Marie Martin, Albert Konijnenberg, Filip Lemière, and Frank Sobott3.1 Introduction 813.2 Sample Preparation 823.3 Electrospray Ionization 843.4 Mass Analyzers and Tandem MS Approaches 883.5 Ion Mobility 903.6 Data Processing 953.7 Challenges and Future Perspectives 98References 102Part II LC–MS Based with Indirect Assays 1094 Methodologies for Effect-Directed Analysis: Environmental Applications, Food Analysis, and Drug Discovery 111Willem Jonker, Marja Lamoree, Corine J. Houtman, and Jeroen Kool4.1 Introduction 1114.2 Principle of Traditional Effect-Directed Analysis 1134.3 Sample Preparation 1134.3.1 Environmental Analysis 1134.3.2 Food Analysis 1214.3.3 Drug Discovery 1244.4 Fractionation for Bioassay Testing 1264.4.1 Environmental Analysis 1264.4.2 Food Analysis 1304.4.3 Drug Discovery 1314.5 Miscellaneous Approaches 1334.6 Bioassay Testing 1364.6.1 Environmental Analysis 1364.6.2 Food Analysis 1404.6.3 Drug Discovery 1404.7 Identification and Confirmation Process 1414.7.1 Instrumentation 1414.7.2 Data Analysis 1434.8 Conclusion and Perspectives 148References 1495 MS Binding Assays 165Georg Höfner and Klaus T.Wanner5.1 Introduction 1655.2 MS Binding Assays – Strategy 1675.2.1 Analogies and Differences Compared to Radioligand Binding Assays 1675.2.2 Fundamental Assay Considerations 1695.2.3 Fundamental Analytical Considerations 1705.3 Application of MS Binding Assays 1715.3.1 MS Binding Assays for the GABA Transporter GAT1 1715.3.2 MS Binding Assays for the Serotonin Transporter 1835.3.3 MS Binding Assays Based on the Quantitation of the Nonbound Marker 1875.3.4 Other Examples Following the Concept of MS Binding Assays 1895.4 Summary and Perspectives 191Acknowledgments 192References 1926 Metabolic Profiling Approaches for the Identification of Bioactive Metabolites in Plants 199Emily Pipan and Angela I. Calderón6.1 Introduction to Plant Metabolic Profiling 1996.2 Sample Collection and Processing 2006.3 Hyphenated Techniques 2036.3.1 Liquid Chromatography–Mass Spectrometry 2036.3.2 Gas Chromatography–Mass Spectrometry 2066.3.3 Capillary Electrophoresis–Mass Spectrometry 2076.4 Mass Spectrometry 2076.4.1 Time of Flight 2086.4.2 Quadrupole Mass Filter 2086.4.3 Ion Traps (Orbitrap and Linear Quadrupole (LTQ)) 2096.4.4 Fourier Transform Mass Spectrometry 2106.4.5 Ion Mobility Mass Spectrometry 2106.5 Mass Spectrometric Imaging 2106.5.1 MALDI-MS 2116.5.2 SIMS-MS 2126.5.3 DESI-MS 2126.5.4 LAESI-MS 2136.5.5 LDI-MS and Others for Imaging 2136.6 Data Analysis 2146.6.1 Data Processing 2146.6.2 Data Analysis Methods 2146.6.3 Databases 2156.7 Future Perspectives 216References 2167 Antivenomics: A Proteomics Tool for Studying the Immunoreactivity of Antivenoms 227Juan J. Calvete, José María Gutiérrez, Libia Sanz, Davinia Pla, and Bruno Lomonte7.1 Introduction 2277.2 Challenge of Fighting Human Envenoming by Snakebites 2277.3 Toolbox for Studying the Immunological Profile of Antivenoms 2287.4 First-Generation Antivenomics 2297.5 Snake Venomics 2307.6 Second-Generation Antivenomics 2327.7 Concluding Remarks 236Acknowledgments 236References 236Part III Direct Pre- and On-Column Coupled Techniques 2418 Frontal and Zonal Affinity Chromatography Coupled to Mass Spectrometry 243Nagendra S. Singh, Zhenjing Jiang, and Ruin Moaddel8.1 Introduction 2438.2 Frontal Affinity Chromatography 2448.3 Staircase Method 2478.4 Simultaneous Frontal Analysis of a Complex Mixture 2498.5 Multiprotein Stationary Phase 2528.6 Zonal Chromatography 2538.7 Nonlinear Chromatography 260Acknowledgments 265References 2659 Online Affinity Assessment and Immunoaffinity Sample Pretreatment in Capillary Electrophoresis–Mass Spectrometry 271Rob Haselberg and Govert W. Somsen9.1 Introduction 2719.2 Capillary Electrophoresis 2729.3 Affinity Capillary Electrophoresis 2769.3.1 Dynamic Equilibrium ACE (Fast Complexation Kinetics) 2769.3.2 Pre-Equilibrium ACE (Slow Complexation Kinetics) 2799.3.3 Kinetic ACE (Intermediate Complexation Kinetics) 2809.4 Immunoaffinity Capillary Electrophoresis 2819.5 Capillary Electrophoresis–Mass Spectrometry 2839.5.1 General Requirements for Effective CE–MS Coupling 2839.5.2 Specific Requirements for ACE–MS and IA-CE-MS 2849.6 Application of ACE–MS 2869.7 Applications of IA-CE–MS 2929.8 Conclusions 295References 29610 Label-Free Biosensor Affinity Analysis Coupled to Mass Spectrometry 299David Bonnel, Dora Mehn, and Gerardo R. Marchesini10.1 Introduction to MS-Coupled Biosensor Platforms 29910.2 Strategies for Coupling Label-Free Analysis with Mass Spectrometry 30110.2.1 On-Chip Approaches 30110.2.2 Off-Chip Configurations 30510.2.3 Chip Capture and Release Chromatography – Electrospray-MS 30610.3 New Sensor and MS Platforms, Opportunities for Integration 30710.3.1 Imaging Nanoplasmonics 30710.3.2 EvanescentWave SiliconWaveguides 30810.3.3 New Trends in MS Matrix-Free Ion Sources 30910.3.4 Tag-Mass 31010.3.5 Integration 310References 310Part IV Direct Post Column Coupled Affinity Techniques 31711 High-Resolution Screening: Post-Column Continuous-Flow Bioassays 319David Falck,Wilfried M.A. Niessen, and Jeroen Kool11.1 Introduction 31911.1.1 Variants of On-line Post-Column Assays Using Mass Spectrometry 32111.1.2 Targets and Analytes 32811.2 The High-Resolution Screening Platform 33011.2.1 Separation 33011.2.2 Flow Splitting 33411.2.3 Bioassay 33611.2.4 MS Detection 34011.3 Data Analysis 34211.3.1 Differences between HRS and HTS 34211.3.2 Validation 35011.4 Conclusions and Perspectives 35311.4.1 The Relation of On-line Post-Column Assays to Other Formats 35311.4.2 Trends in High-Resolution Screening 35411.4.3 Conclusions 357References 35812 Conclusions 365Jeroen KoolIndex 373

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