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Experimental Approaches of NMR Spectroscopy - Methodology and Application to Life Science and Materials Science
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Experimental Approaches of NMR Spectroscopy - Methodology and Application to Life Science and Materials Science
von: The Nuclear Magnetic Resonance Society of Japan
Springer-Verlag, 2017
ISBN: 9789811059667
634 Seiten, Download: 23141 KB
 
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Inhaltsverzeichnis

  Member of the Editorial Board 5  
  Preface 6  
  Acknowledgements 8  
  Contents 9  
  Methodology 11  
  1 Protein Studies by High-Pressure NMR 12  
     Abstract 12  
     1.1 Introduction 12  
        1.1.1 The NMR Spectroscopy and Its Limitation 13  
        1.1.2 Overcoming the Limitation with Pressure 15  
        1.1.3 Turning NMR “Invisible” Conformers into NMR “Visible” with Pressure 16  
     1.2 The Thermodynamic Background 19  
        1.2.1 Effect of Pressure on the Protein Conformational Equilibrium 19  
        1.2.2 “Volume” Decreases as “Cavity” Hydration Increases 21  
        1.2.3 The “Volume ??Theorem”?? of Protein and the High-Pressure NMR Experiment 23  
     1.3 Apparatus for High-Pressure NMR Experiments 24  
        1.3.1 The Autoclave Method 25  
        1.3.2 The Pressure-Resisting Cell Method 25  
     1.4 Application to Protein Studies 28  
        1.4.1 Fluctuations within the Basic Folded Ensemble 29  
           1.4.1.1 Fluctuation in Individual Hydrogen Bonds Detected by 1H Pressure Shifts 30  
           1.4.1.2 Residue-Specific Fluctuations of the Polypeptide Chain Conformation Detected by 15N/1H Pressure Shifts 32  
           1.4.1.3 Slow Cooperative Fluctuations Detected by Ring-Flip Motions 34  
        1.4.2 Fluctuations into Alternately Folded Conformer 35  
        1.4.3 Conformational Fluctuations Involving Fibril Formation and Dissociation 35  
           1.4.3.1 Cause for Familial Amyloidotic Polyneuropathy 36  
           1.4.3.2 Conformational Fluctuations in Prion Protein and Drugs to Prevent Fibrillation 37  
           1.4.3.3 Amyloid Fibril Is a High-Volume State 39  
           1.4.3.4 Fibril Formation Is Part of the Intrinsic Conformational Fluctuation of Proteins 39  
        1.4.4 Exploring the Protein Folding Pathway with High-Pressure NMR 40  
     1.5 Summary: Perspectives of High-Pressure NMR Spectroscopy 41  
     References 42  
  2 Isotope-Aided Methods for Biological NMR Spectroscopy: Past, Present, and Future 46  
     Abstract 46  
     2.1 Historical Background of Our Research to Develop Isotope-Aided NMR Methods 47  
        2.1.1 Stereo-Specific Deuteration of Prochiral Methylene Protons—Conformational Analysis of Amino Acids and Peptides 48  
        2.1.2 Selective 13C, 15N Double-Labeling Method for the Sequential Assignment of Backbone Amide NMR Signals in Large Proteins 49  
        2.1.3 Revisiting the Stereo-Specific Isotope-Labeling Approach for Studying Proteins: A Long March to the SAIL Method 51  
     2.2 The SAIL Method: An Optimized Isotope-Labeling Strategy for the Structural Study of Proteins by NMR Spectroscopy 51  
        2.2.1 Cell-Free Expression and NMR Spectra of SAIL Proteins 53  
        2.2.2 Structural Determination of SAIL Proteins 56  
     2.3 Recent Trends in the Isotope-Aided NMR Methods for Studying Proteins 58  
        2.3.1 Residue- and Stereo-Specific Labeling Method: The Case for Leu and Val Methyl Labeling of Larger Proteins 59  
        2.3.2 Large-Amplitude Dynamics of Proteins as Probed by Aromatic Ring-Flipping Motions—The Case for the Interface Between FKBP and Drug Complexes 61  
        2.3.3 Deuterium-Induced Isotope Shifts for Measuring Hydrogen Exchange Rates of Polar Side-Chain Groups in Proteins: Facile Screening of the Polar Groups Involved in Hydrogen Bond Networks 64  
     2.4 Future Perspectives of the Isotope-Aided NMR Method 66  
     Acknowledgements 66  
     References 67  
  3 Advances in NMR Data Acquisition and Processing for Protein Structure Determination 71  
     Abstract 71  
     3.1 Advances in Processing of Multi-dimensional NMR Spectra, and Their Application to Rapid NMR Measurements 72  
        3.1.1 Multi-dimensional NMR Takes Time 72  
        3.1.2 Processing of Multi-dimensional NMR Spectra 73  
        3.1.3 Rapid Measurement of Multi-dimensional NMR Spectra 75  
        3.1.4 Non-uniform Sampling 76  
        3.1.5 NUS Sampling Schemes 77  
        3.1.6 Semi-constant-Time Evolution Periods 79  
        3.1.7 Conclusions 82  
     3.2 Data Analysis for Protein Structure Determination 82  
        3.2.1 Chemical Shift Data Analysis 82  
        3.2.2 NOE Data Analysis 85  
        3.2.3 NMR Protein Structure Determination Based on Bayesian Inference 88  
        3.2.4 Hybrid Method with Small-Angle Scattering (SAS) 92  
        3.2.5 Conclusions 94  
     Acknowledgements 94  
     References 95  
  4 Advances in High-Field DNP Methods 99  
     Abstract 99  
     4.1 Introduction 100  
     4.2 Overview of a DNP-NMR System 101  
     4.3 DNP Mechanisms and Polarizing Agents 101  
     4.4 SMMW Sources and Transmission Systems 107  
        4.4.1 Various Light Sources and Gyrotron 107  
        4.4.2 Principles of Gyrotron 109  
        4.4.3 Operation of Gyrotron 112  
        4.4.4 Transmission of SMMW 116  
        4.4.5 Feedback Regulation of SMMW 117  
        4.4.6 Double SMMW Irradiation 119  
     4.5 DNP-NMR Probes and Low-Temperature Facilities 120  
        4.5.1 MAS at Cryogenic Temperatures 120  
        4.5.2 SMMW Irradiation of Sample 122  
        4.5.3 Production of Cryogenic Spinner Gas 125  
     4.6 DNP Samples and Recent Applications 128  
        4.6.1 Basic Setup 128  
        4.6.2 Sample Preparation and DNP Efficiency 130  
        4.6.3 DNP Enhancement Factor and Temperature 134  
     4.7 Summary and Outlook 135  
     Acknowledgements 136  
     References 136  
  5 Photoirradiation and Microwave Irradiation NMR Spectroscopy 143  
     Abstract 143  
     5.1 Introduction 144  
        5.1.1 Photoirradiation Solid-State NMR Spectroscopy 144  
        5.1.2 Microwave Irradiation NMR Spectroscopy 145  
     5.2 Experimental Details for Photoirradiation Solid-State NMR Spectroscopy 146  
        5.2.1 Photoirradiation System for Solid-State NMR 146  
        5.2.2 Photoirradiation NMR Measurements 146  
        5.2.3 Detection of Photo-Intermediates in the Photoreaction Cycles 147  
     5.3 Photoreaction Cycle for SRI as Revealed by In Situ Photoirradiation Solid-State NMR 148  
     5.4 The Photoreaction Cycle of Pharaonis Phoborhodopsin (SRII) as Revealed by Photoirradiation Solid-State NMR Spectroscopy 152  
     5.5 The Photoreaction Pathway for the Bacteriorhodopsin Y185F Mutant 154  
     5.6 Experimental Details for Microwave Irradiation NMR Spectroscopy 156  
        5.6.1 In Situ Microwave Irradiation NMR Spectrometer 156  
        5.6.2 Temperature Measurements 157  
        5.6.3 Microwave Temperature Jump Experiments 158  
     5.7 Microwave Heating Effect of MBBA 159  
        5.7.1 Microwave Heating Effect of MBBA in the Liquid Crystalline State 159  
        5.7.2 Microwave Heating Effect of MBBA in the Isotropic State 160  
        5.7.3 Mechanism for Microwave Heating of Liquid Crystalline MBBA 162  
        5.7.4 Mechanism for Microwave Heating of Isotropic Phase MBBA 163  
     5.8 Experimental Details for SC-2D NMR Spectroscopy 164  
     5.9 SC-2D NMR Spectra of Liquid Crystalline Samples 165  
        5.9.1 SC-2D NMR Measurements of APAPA 165  
        5.9.2 Interpretation of the Cross-sectional Spectra from SC-2D NMR Experiments 168  
        5.9.3 Interpretation of the Dipolar Patterns of the Aromatic and Methyl Protons 170  
        5.9.4 Interpretation of the Cross-Sectional Patterns 171  
     5.10 Conclusions 173  
     Acknowledgements 174  
     References 174  
  6 Solid-State NMR Under Ultrafast MAS Rate of 40–120 kHz 179  
     Abstract 179  
     6.1 Overview 179  
     6.2 Setup of Sample-independent Factors 182  
        6.2.1 Shimming 182  
        6.2.2 Magic-Angle Adjustment 184  
        6.2.3 rf Field Strength Calibration 185  
        6.2.4 Reference 187  
     6.3 Sample-Dependent Setup 188  
        6.3.1 Relaxation Delay 188  
        6.3.2 Hardware Treatment 191  
     6.4 Setup of 2D Measurements 192  
        6.4.1 1H DQ/SQ Correlation 192  
        6.4.2 1H-detected 1H/X CP-HSQC 196  
     6.5 Conclusions 198  
     Acknowledgements 199  
     References 199  
  7 Elucidating Functional Dynamics by R1? and R2 Relaxation Dispersion NMR Spectroscopy 204  
     Abstract 204  
     7.1 Relaxation Dispersion 205  
     7.2 Accessible Information 206  
     7.3 R1? Relaxation Dispersion 207  
        7.3.1 General Aspects 207  
        7.3.2 Pulse Sequence of the R1? Relaxation Dispersion Experiment 208  
        7.3.3 Automation of R1? Relaxation Dispersion Measurements and Data Processing 211  
           7.3.3.1 Experimental Setup 211  
           7.3.3.2 Screening 212  
           7.3.3.3 Processing 213  
     7.4 R2 Relaxation Dispersion 214  
        7.4.1 General Aspects 214  
        7.4.2 Quantifying Protein–Ligand Interactions by R2 Relaxation Dispersion 215  
           7.4.2.1 Theory 216  
           7.4.2.2 Example 1: Interaction Between the pKID Domain of CREB and the KIX Domain of CBP/p300 217  
           7.4.2.3 Example 2: Interaction Between the Transactivation Domain of c-Myb and KIX 219  
     7.5 Fitting of the Relaxation Rates to a Theoretical Model 219  
        7.5.1 Least-Squares Fitting in GLOVE 219  
        7.5.2 Monte Carlo Minimization Algorithm in GLOVE 221  
        7.5.3 Two-State Exchange 221  
        7.5.4 Workflow for Processing Relaxation Dispersion Data in GLOVE 223  
        7.5.5 Examples of Relaxation Dispersion Curve Fitting by GLOVE 224  
     7.6 Outlook 226  
     References 227  
  8 Structural Study of Proteins by Paramagnetic Lanthanide Probe Methods 233  
     Abstract 233  
     8.1 Introduction 234  
     8.2 Structural Information Obtained from Paramagnetic Lanthanide Probe Methods 234  
        8.2.1 Pseudocontact Shift (PCS) 235  
        8.2.2 Residual Dipolar Coupling (RDC) 235  
        8.2.3 Paramagnetic Relaxation Enhancement (PRE) 237  
     8.3 Various Magnetic Properties of Lanthanide Ions 238  
     8.4 Application of the Paramagnetic Lanthanide Probe in Protein Structural Studies 239  
        8.4.1 Caged Lanthanide NMR Probe 5 (CLaNP-5) 240  
        8.4.2 Two-Point Anchored Lanthanide-Binding Peptide Tag (LBT) 241  
     8.5 Measurement and Analysis of Anisotropic Paramagnetic Effects 245  
     8.6 Use of Paramagnetic Effects in Protein Structural Studies 246  
        8.6.1 PCS-Based Docking for Protein–Protein Complexes 246  
        8.6.2 Evaluation of the Conformational Changes in a Multi-domain Protein 248  
        8.6.3 Further Applications of Paramagnetic Lanthanide Probe Methods 249  
     8.7 Concluding Remarks 251  
     Acknowledgements 252  
     References 252  
  9 Structure Determination of Membrane Peptides and Proteins by Solid-State NMR 259  
     Abstract 259  
     9.1 Introduction 260  
     9.2 Experimental Approaches Used in Solid-State NMR Spectroscopy 260  
        9.2.1 Experimental Details for Obtaining the Structures of Membrane-Associated Peptides and Proteins Using Anisotropic Interactions 261  
           9.2.1.1 Orientation Dependence of Chemical-Shift Interaction 261  
           9.2.1.2 Orientation Dependence of Nuclear Dipolar Interactions 266  
           9.2.1.3 Interatomic Distance Measurements by REDOR 267  
              Simple Description of the REDOR Experiment 267  
              Rotational Echo Amplitude by the Density Operator Approach 269  
              Echo Amplitude in Three-Spin System (S1-I1-S2) 271  
              Practical Aspects of a REDOR Experiment 272  
        9.2.2 Magic-Angle Spinning NMR 274  
           9.2.2.1 CP-MAS NMR 274  
           9.2.2.2 Correlation NMR Spectroscopy 275  
           9.2.2.3 PDSD and DARR 2D NMR Spectroscopy 275  
     9.3 Structure Determination of Membrane-Bound Peptides 277  
        9.3.1 Melittin 277  
        9.3.2 Alamethicin 283  
        9.3.3 Bovine Lactoferrampin 284  
     9.4 Structure Determination of Membrane Proteins 287  
     9.5 Conclusion 291  
     Acknowledgements 293  
     References 293  
  Application to Life Science and Materials Science 300  
  10 NMR Studies on Silk Materials 301  
     Abstract 301  
     10.1 Introduction 301  
     10.2 Results and Discussion 302  
        10.2.1 Dynamics of Silk Fibroin Stored in Living Silkworm 302  
        10.2.2 Solution Structure of Silk Fibroin at Atomic Level 304  
        10.2.3 Dynamics of Water Molecules Interacted with Silk Fibroin 305  
        10.2.4 Dynamics of Hydrated Silk Cocoon, Sericin, and Fibroin 307  
        10.2.5 Fraction of Several Conformations of Silk Fibroin 308  
        10.2.6 Domain of Silk Fibroin 309  
        10.2.7 Inter-molecular Arrangement of Alanine Oligopeptide 310  
        10.2.8 Complex between Silk Fibroin and Glycerin 310  
        10.2.9 Use of Chemical Shift Calculation for Verification of Silk Fibroin Structural Model 312  
     10.3 Conclusion 313  
     References 314  
  11 NMR Studies on Polymer Materials 317  
     Abstract 317  
     11.1 Introduction 318  
     11.2 Polymer Blends and Alloys 318  
        11.2.1 Miscibility and Mobile Heterogeneity 318  
           11.2.1.1 PS/PVME Blends 320  
           11.2.1.2 PMAA/PVAc Blends 323  
           11.2.1.3 PK/PA Alloys 325  
        11.2.2 Phase Separation 328  
           11.2.2.1 PS/PVME Blends 328  
           11.2.2.2 P3HT/PCBM Blends 330  
     11.3 Polymer Nanocomposites 332  
        11.3.1 Paramagnetic Effect on Relaxation 332  
           11.3.1.1 PVA/Montmorillonite Clay Nanocomposites 332  
           11.3.1.2 Nylon-6/mmt Nanocomposites 333  
        11.3.2 Interaction Between Polymers and Fillers 334  
           11.3.2.1 Nylon-6/Montmorillonite Clay Nanocomposites 334  
           11.3.2.2 PS-PEO Block Copolymer/Hectorite Clay Nanocomposites 335  
        11.3.3 Morphology 336  
           11.3.3.1 PVIBE/?-PL/Saponite Clay Blends 336  
           11.3.3.2 Nylon-6/Montmorillonite Clay Nanocomposites 337  
     11.4 Rubbers and Elastomers 339  
     11.5 Conclusion 340  
     References 341  
  12 Solid-State 2H NMR Studies of Molecular Motion in Functional Materials 344  
     Abstract 344  
     12.1 Introduction 345  
     12.2 Measurements of Solid-State 2H NMR Spectrum 345  
     12.3 Simulation Methods of Solid-State 2H NMR Spectrum 347  
     12.4 Analysis of MOF/PCP 354  
     12.5 Analysis of Solid Proton-Conducting Material 356  
     12.6 Analysis of Spin-Crossover Material 361  
     12.7 Summary 365  
     References 366  
  13 NMR Spectral Observations of the Gases in Polymer Materials 368  
     Abstract 368  
     13.1 Introduction 368  
     13.2 Basics of the NMR Analysis of Gas–Polymer Systems 369  
        13.2.1 Apparatus for the Preparation of NMR Sample Tubes Containing High-Pressure Gas Samples 369  
        13.2.2 Gas Sorption Properties of Polymers 370  
     13.3 Characterization of the High-Order Structure of a Glassy Polymer Based on 129Xe NMR Chemical Shifts 372  
     13.4 Characterization of the High-Order Structure of Rubbery Polymers from 129Xe NMR Chemical Shifts 374  
     13.5 Analysis of Gas Diffusion Characteristics in Polymers Based on NMR Peak Width 376  
     13.6 Characterization of Oriented Structures by Pulsed Field Gradient NMR 379  
     13.7 Summary 382  
     References 382  
  14 NMR Studies on Natural Product—Stereochemical Determination and Conformational Analysis in Solution and in Membrane 385  
     Abstract 385  
     14.1 Stereochemical Determination of Natural Products 386  
        14.1.1 JBCA Method 387  
        14.1.2 UDB Method 392  
        14.1.3 Calculations 394  
        14.1.4 RDCs 398  
     14.2 NMR Methods for Examining the Conformation and Intermolecular Interactions of Natural Products in Membranes 401  
        14.2.1 Amphotericin B 402  
        14.2.2 Erythromycin A 406  
        14.2.3 Theonellamide A 407  
     14.3 Summary and Outlook 412  
     Acknowledgements 412  
     References 412  
  15 Technical Basis for Nuclear Magnetic Resonance Approach for Glycoproteins 417  
     Abstract 417  
     15.1 Introduction 418  
     15.2 Enigmatic Aspects of Carbohydrate Structures 418  
     15.3 Expression of Isotope-Labeled Glycoproteins 420  
     15.4 Glycosylation Profiling 425  
     15.5 Remodeling of Glycoprotein Glycoforms 426  
     15.6 Spectral Observations and Assignments 430  
     15.7 NMR Analyses of Dynamic Conformations and Interactions of Oligosaccharides 432  
     15.8 Perspectives 434  
     Acknowledgements 435  
     References 435  
  16 NMR Studies on RNA 441  
     Abstract 441  
     16.1 Design of RNA Sequences 441  
     16.2 Sample Preparation 442  
        16.2.1 In Vitro Transcription 444  
        16.2.2 Chemical Synthesis 444  
        16.2.3 Enzymatic Ligation 445  
        16.2.4 Artificial Base Pair System 445  
        16.2.5 Stable Isotopic Labelling 446  
        16.2.6 Purification 446  
     16.3 Measurements 447  
        16.3.1 Exchangeable Protons 447  
        16.3.2 Non-exchangeable Protons 449  
        16.3.3 Residual Dipolar Coupling 449  
     16.4 Signal Assignments 451  
        16.4.1 Exchangeable Protons 451  
        16.4.2 Non-exchangeable Protons 451  
     16.5 Structural Calculation 455  
     16.6 Interaction Analysis and Structure Screening 457  
     16.7 Perspective 459  
     References 459  
  17 NMR Analysis of Molecular Complexity 462  
     Abstract 462  
     17.1 Introduction 463  
     17.2 Metabolomics and Metabolic Profiling for Small Molecular Complexity 463  
        17.2.1 Basic Knowledge for Small Molecular Profiling 463  
        17.2.2 Experimental Aspects of Sample Preparation 464  
        17.2.3 NMR Measurements and Data Processing 466  
           17.2.3.1 Useful Pulse Sequences 466  
           17.2.3.2 Databases and Tools for NMR Analysis 467  
           17.2.3.3 Signal Assignments and Structure Elucidation 467  
           17.2.3.4 Spectral Pretreatment for Data Science 470  
           17.2.3.5 Practical Aspects of Data Science 471  
        17.2.4 Applications to Plant, Animal, and Microbial Systems 471  
           17.2.4.1 Application to Plant Systems 471  
           17.2.4.2 Application to Animal Systems 472  
           17.2.4.3 Application to Microbial Systems 473  
     17.3 Biomass Profiling for Macromolecular Complexity 474  
        17.3.1 Basic Knowledge for Macromolecular Profiling 474  
        17.3.2 Experimental Aspects of Sample Preparation 474  
        17.3.3 NMR Measurements and Data Processing 476  
           17.3.3.1 Useful Pulse Sequences 476  
              Peak Separation for Broad Macromolecular Spectra 478  
        17.3.4 Applications to Material, Biological, and Geochemical Systems 479  
           17.3.4.1 Application to Cellulosic Material Systems 479  
           17.3.4.2 Application to Biological Systems 480  
           17.3.4.3 Application to Geochemical Samples 482  
     17.4 Future Perspectives 483  
     References 483  
  18 NMR of Paramagnetic Compounds 491  
     Abstract 491  
     18.1 Introduction 491  
     18.2 Paramagnetic Effects 494  
        18.2.1 Paramagnetic Shifts 494  
        18.2.2 Paramagnetic Relaxation 495  
     18.3 1H NMR Spectra of Myoglobin with 0, 1, 4, or 5 Unpaired Electrons 498  
        18.3.1 Overview 498  
        18.3.2 Diamagnetic Carbonmonoxy Form [Mb(CO)] 499  
        18.3.3 Paramagnetic Deoxy Form (Deoxy Mb) with S = 2 499  
        18.3.4 Paramagnetic Met-Cyano Form [MetMb(CN?)] with S = ½ 502  
        18.3.5 Paramagnetic Met-Azido Form [MetMb(N3?)] with Mainly S = ½ 504  
        18.3.6 Paramagnetic Met-Aquo Form [MetMb(H2O)] with S = 5/2 505  
     18.4 NMR Measurements 506  
        18.4.1 NOEs in Paramagnetic Compounds 506  
        18.4.2 Hydrogen Exchange Rates 509  
     18.5 Concluding Remarks 512  
     Acknowledgements 513  
     References 513  
  19 NMR of Quadrupole Nuclei in Organic Compounds 519  
     Abstract 519  
     19.1 Introduction 519  
     19.2 Theoretical Background of Quadrupole Interactions 520  
     19.3 Simulating Solid-State NMR of Quadrupole Nuclei Based on the Perturbation Method 522  
        19.3.1 Stationary NMR Spectra Under the Influence of Second-Order Quadrupole Interactions 524  
        19.3.2 Fast MAS NMR Conditions Under the Influence of Second-Order Quadrupole and CS Interactions 527  
        19.3.3 Stationary NMR Spectra Under the Influence of Second-Order Quadrupole and CS Interactions 530  
     19.4 Solid-State NMR of Quadrupole Nuclei Based on Direct Calculation Methods 534  
     19.5 Conclusions 541  
     References 542  
  20 Quadrupole Nuclei in Inorganic Materials 544  
     Abstract 544  
     20.1 Introduction 545  
     20.2 Anisotropy of Quadrupolar Interaction 546  
     20.3 Orientation Dependence of Quadrupolar Interaction 552  
     20.4 Signal Separation Through Quadrupolar Coupling 557  
        20.4.1 MQMAS 558  
        20.4.2 STMAS 561  
     20.5 Signal Separation Through Correlations to Other Nuclei 561  
     20.6 Sensitivity Enhancement Through Population Transfer 565  
     20.7 Confronting the Real World, Real Materials 567  
     Acknowl?edge??ments 572  
     References 572  
  21 Protein–Ligand Interactions Studied by NMR 577  
     Abstract 577  
     21.1 Overview 578  
     21.2 Ligand-Based Approach 578  
        21.2.1 Ligand Screening 581  
           21.2.1.1 Saturation Transfer Difference (STD) 581  
           21.2.1.2 WaterLOGSY 581  
           21.2.1.3 STD Versus WaterLOGSY 582  
        21.2.2 Pharmacophore Determination 582  
           21.2.2.1 DIRECTION 583  
           21.2.2.2 INPHARMA 583  
        21.2.3 Structural Information-Driven Ligand Design 584  
           21.2.3.1 Inter-ligand Nuclear Overhauser Effect (ILOE) 585  
           21.2.3.2 Transferred Nuclear Overhauser Effect (trNOE) 585  
           21.2.3.3 Technical Comments on INPHARMA, ILOE and trNOE Experiments 586  
     21.3 Protein-Based Approach for Protein–Ligand Interactions 586  
        21.3.1 Ligand Screening and NMR-Assisted Fragment-Based Drug Discovery 588  
           21.3.1.1 HSQC-Based Ligand Screening 588  
           21.3.1.2 SAR-by-NMR 589  
        21.3.2 Determination of the Molecular Interface and Exploring the Mode of Action 589  
           21.3.2.1 Chemical Shift Mapping 589  
           21.3.2.2 KD Determination by the NMR Titration 590  
     21.4 Experimental Aspects of the NMR Study of Protein–Ligand Interactions 591  
        21.4.1 Stable Isotope Labeling 591  
        21.4.2 Tips for the NMR Titration Experiment 592  
           21.4.2.1 Sample Handling 592  
           21.4.2.2 Data Acquisition and Analysis 594  
     21.5 Other Complementary Methods for Protein–Ligand Interactions 594  
     21.6 Perspective 595  
     References 595  
  22 Protein Structure and Dynamics Determination by Residual Anisotropic Spin Interactions 599  
     Abstract 599  
     22.1 Why Do We Need Residual Anisotropic Nuclear Spin Interactions in Solution NMR? 600  
     22.2 Theoretical Backgrounds of the Residual Anisotropies 602  
        22.2.1 Residual Dipolar Coupling, RDC 603  
        22.2.2 Theoretical Description on RDC 605  
        22.2.3 Residual Chemical Shift Anisotropy, RCSA 608  
     22.3 Practical Procedures to Use the Residual Anisotropies 611  
        22.3.1 Magnetically Aligning Liquid Crystalline Media 611  
        22.3.2 Naturally Occurring Materials that Spontaneously Align in a Magnetic Field 613  
        22.3.3 Compressed Acryl Amide Gel 613  
        22.3.4 Protein Structures in Weakly Aligned Media 615  
     22.4 RDC-Based Domain Orientation Analysis 616  
        22.4.1 Collecting the RDC Data 617  
        22.4.2 Domain Orientation Analysis Based on the RDC Data 617  
        22.4.3 Significance of the Domain Orientation Analysis by RDCs 619  
        22.4.4 Molecular Size Limitation in the RDC-Based Approach 619  
        22.4.5 Existing Remedy for Overcoming the Size Limitation in the RDC-Based Approach 621  
     22.5 Alignment Tensor Determination Using Only TROSY 622  
        22.5.1 Alignment-Induced TROSY Shift Changes 622  
        22.5.2 CSA Tensor Parameters Used in DIORITE 624  
        22.5.3 DIORITE Analysis Using Different Magnetic Field Strengths 625  
        22.5.4 Practical Aspects of the DIORITE Data Collection 627  
        22.5.5 DIORITE Analyses on MBP in Different Ligand Bound States 628  
     22.6 Conclusion 630  
     References 631  


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