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Published on 18 May 2017 on http://pubs.rsc.org | doi:10.1039/9781782628361-FP001
Beyond the Fourier Transform

Fast NMR Data Acquisition
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New Developments in NMR
Editor-in-chief:
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Series editors:
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Bruce Balcom, University of New Brunswick, Canada
István Furó, Industrial NMR Centre at KTH, Sweden
Masatsune Kainosho, Tokyo Metropolitan University, Japan
Maili Liu, Chinese Academy of Sciences, Wuhan, China
Titles in the series:

1: Contemporary Computer-Assisted Approaches to Molecular Structure
Elucidation
2: New Applications of NMR in Drug Discovery and Development
3: Advances in Biological Solid-State NMR
4: Hyperpolarized Xenon-129 Magnetic Resonance: Concepts, Production,
Techniques and Applications
5: Mobile NMR and MRI: Developments and Applications
6: Gas Phase NMR
7: Magnetic Resonance Technology: Hardware and System
Component Design
8: Biophysics and Biochemistry of Cartilage by NMR and MRI
9: Diffusion NMR of Confined Systems: Fluid Transport in Porous Solids
and Heterogeneous Materials
10: NMR in Glycoscience and Glycotechnology
11: Fast NMR Data Acquisition: Beyond the Fourier Transform
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Fast NMR Data Acquisition

Beyond the Fourier Transform
Edited by
Mehdi Mobli
The University of Queensland, Brisbane, Australia
Email: m.mobli@uq.edu.au
and
Jeffrey C. Hoch
UConn Health, Farmington, CT, USA
Email: hoch@uchc.edu
Published on 18 May 2017 on http://pubs.rsc.org | doi:10.1039/9781782628361-FP001 View Online
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Foreword
Few branches of spectroscopy match the versatility, applicability and im-

plications of Magnetic Resonance. In its molecular analysis mode, NMR, it
provides structural and dynamic information in the widest range of situ-
ations: solids, organics, pharmaceuticals, proteins and nucleic acids, cells,
and metabolism in living organisms. In its imaging mode, MRI, it provides
one of the most widely used forms for understanding biological function
and for non-invasive diagnosis of disease. A common denominator of nearly
all contemporary NMR and MRI experiments relates to their need to unravel
complex, overlapping information. This challenge is solved via one of
magnetic resonance’s most insightful propositions: the multidimensional
NMR/MRI experiment. By spreading and correlating information onto sev-
eral dimensions, multidimensional NMR/MRI stands as one of the intel-
lectual jewels of modern spectroscopy. While originally proposed by Jeener
as a tool to assign J-coupled peaks in a spectrum, Ernst and others rapidly
realized the value of multidimensional magnetic resonance to obtain images
of opaque objects, to detect invisible coherence states, to provide the reso-
lution needed to elucidate complex chemical systems, and to determine the
spatial structure of biological machines under near physiological conditions.
Multidimensional approaches have since been adopted by other branches of
spectroscopy—electron paramagnetic resonance, mass spectrometry, IR and
visible optics—and thereby taken an additional number of unique roles in
chemistry and biochemistry. But in no area of scientific research have
multidimensional experiments retained such central roles as in NMR and
MRI. Just to give an idea of the breadth of these applications, suffice it to
mention that 2D-mediated observations of radiation-less multiple-quantum
transitions is essential to understand the structure of complex materials,
that 2D correlations between distant nuclei in small molecules often serve as
the ‘‘eyes’’ with which organic and pharmaceutical chemists identify their

Fast NMR Data Acquisition: Beyond the Fourier Transform
Edited by Mehdi Mobli and Jeffrey C. Hoch
Published by the Royal Society of Chemistry, www.rsc.org
v
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vi Foreword
1
products, that correlations of low-g evolutions with H spin detection have
been essential to endow NMR with the sensitivity needed by the structural
biologist seeking to understand biochemical function in situ, that tens of
millions of yearly 3D MRI scans are at the core of radiological exams pre-
venting and treating the widest range of maladies, and that neither biology’s
nor psychology’s contemporary understanding of living bodies and minds

would stand where they do today without multidimensional functional MRI
correlations.
Despite these invaluable and extraordinarily diverse roles of one and the
same experiment, a grand challenge stands in the road of these MR imple-
mentations: the additional time that multidimensional experiments de-
mand vis-à-vis their 1D counterparts. This is a demand that was ‘‘built-in’’
and accepted from the genesis of these methods onwards, but which is often
onerous and far from inconsequential. Indeed, extended acquisitions have a
penalty that goes far beyond the ‘‘time is money’’ concept: by increasing
their duration in a manner that grows exponentially with the number of
dimensions involved, high-dimensional experiments on the complex sys-
tems on which they are most essential rapidly become incompatible with
their practical realization. Complex systems tend to have a dynamics of their
own, and can rarely withstand extremely long examinations in their natural
conditions. In few instances did this become as apparent as in the medical
applications of MR, where it was clear that often infirm patients could not be
subject to high-definition three- or four-dimensional acquisitions lasting for
hours on end. This triggered a slow but steady departure from the discrete
Fourier transform principles that dominated the nD MRI acquisition over its
first two decades. To this end, phycisists joined efforts with computer sci-
entists, leading eventually to the kind of sparse sampling techniques that
nowadays enable the delivery of 2563 or 5123 3D images in a matter of
minutes. These principles are finding an increased translation into NMR
experiments, suffering as they do from the additional sensitivity penalties
associated with lower spin concentrations and to mixing processes that,
active in-between the various dimensions, tax this kind of acquisition even
further. The results of these efforts within the field of NMR, particularly as
they have shaped over the last decade, are summarized in the pages of this
monograph. These include the use of fast-switching gradients to unravel
indirect spectral dimensions, the introduction of regularization procedures
in order to bypass the otherwise overtly strict sampling demands of the fast
Fourier transform algorithm, the joint sampling of multiple dimensions in a
‘‘back-projected’’ fashion, and the design of metrics to assess the reliability
of all these techniques. Coming to the aid of the much lower sensitivities
characterizing NMR vis-à-vis MRI are relaxation-enhanced methods, which
over recent years have become an indispensible tool in multidimensional
biomolecular NMR.
While it is clear that accelerated nD NMR acquisitions are rapidly become
a mature topic, I would like to challenge the reader by venturing to say
that their final form is far from settled. Additional improvements and
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Foreword vii
combinations of new spin physics and data processing will surely keep en-
hancing the performance of high-dimensional NMR, including perhaps
spectroscopic-oriented analogues of common MRI modalities, such as multi-
band excitations and parallel receiving, which so far have not received all the
NMR attention they might deserve. Furthermore, it is unlikely that one
single approach will fit best the hundreds of multidimensional experiments

normally used in solid and solution phase NMR—a diversity that in both
dimensions and interactions is much higher than that occupying our MR
imaging colleagues. I therefore conclude by thanking the authors and edi-
tors of this volume for offering its material as timely ‘‘food for thought’’,
while encouraging all of us to read these pages with a critical, open mind.
Chances are that the ultimate treatise on fast multidimensional NMR still
remain to be written. . .
Lucio Frydman
Rehovot
Preface
NMR spectroscopy is ubiquitous in structural elucidation of synthetic

compounds, metabolites, natural products and materials in chemistry, as
well as structural and functional characterisation of biomolecules and
macromolecular complexes. The versatility of NMR spectroscopy derives
from multiple-pulse experiments, where nuclear correlations are encoded in
multidimensional spectra. However, the direct result of an NMR experiment
is not a spectrum, but a time series. The NMR spectrum is generated from
the time response of the pulsed experiment through the application of a
method for spectrum analysis, which constructs a frequency-domain spec-
trum from, or consistent with, the time-domain empirical data. Signal pro-
cessing and pulsed NMR therefore go hand-in-hand in modern NMR
spectroscopy. The inherently weak NMR signal has made signal processing a
vital step in the varied applications of NMR. Basic understanding of signal
processing is therefore a pre-requisite for the modern NMR spectroscopist.
In recent years we have witnessed an explosion in the variety of methods
for spectrum analysis employed in NMR, motivated by limitations of the
discrete Fourier transform (DFT) that was seminal in the development of
modern pulsed NMR experiments. Prime among these limitations is the
difficulty (using the DFT) of obtaining high-resolution spectra from short
data records. An inherent limitation of the DFT is the requirement that data
be collected at uniform time intervals; many modern methods of spectrum
analysis circumvent this requirement to enable much more efficient
sampling approaches. Other modern methods of spectrum analysis obtain
high-resolution spectra by implicitly or explicitly modelling the NMR signals.
Alternatively, we have witnessed the development of approaches that collect
multidimensional data via multiplexing in space—exploiting the physical
dimensions of the sample—rather than via sampling a series of indirect time
dimensions, or approaches that tailor the pulse sequence in ways that enable

viii
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Preface ix
drastically faster sampling in time. Together, methods based on nonuniform

sampling in time or sampling in space enable a class of experiments de-
scribed as Fast NMR Data Acquisition. The methods that increase the speed
of data acquisition through non-conventional pulse sequence design include
SOFAST-NMR and Single Scan NMR, covered in the first two chapters of this
book. Methods based on modelling the signal to obtain high resolution

spectra from short data records or those that support nonuniform sampling
are described in Chapters 3–4 and Chapters 5–10, respectively. The latter
are further categorized by those that sample in a deterministic matter,
i.e. uniformly along radial or concentric patterns (Chapters 5 and 6) or
those that seek incoherence in the distribution of the sampling times
(Chapters 7–10).
In this book we have brought together contributions from leading
scientists in the development of Fast NMR Data Acquisition to provide a
comprehensive reference text on this rapidly growing field. The popularity
and rapid expansion of fast acquisition methods is evident in the literature.
For example, a search for non-uniform sampling (NUS) terms (non-uniform,
non-linear, projection, radial, etc.) and NMR revealed 185 publications since
2000 (Scopus). 13 of these were published between 2000 and 2005, when
projection reconstruction and reduced dimensionality experiments were
being developed. In 2005–2010 the impact of these experiments and their
relationship to data sampling led to 44 publications, and in 2010–2015 the
field further expanded with 105 publications, with the introduction of
various ‘‘compressed sensing’’ techniques and the elucidation of their re-
lationship to established methods. Similarly, citations of these articles have
risen from 237 citations in 2010 to B800 citations in 2015. These numbers,
although crude, nevertheless show how interest in fast acquisition techni-
ques has exploded over the past two decades, moving from relative obscurity
to the mainstream. The widespread adoption of Fast Acquisition Methods is
perhaps most evident in the rapid adaptation of modern spectrometers
to these methods. In 2005, purpose-written pulse sequences had to be used
to perform NUS, whilst today it is treated as simply another standard ac-
quisition parameter during experimental setup by most commercial NMR
instruments.
There is no doubt that fast acquisition methods are now firmly established
as a part of modern NMR spectroscopy and we hope that this text book will
serve to orient the spectroscopist in this new era, providing improved
understanding of the many methods on offer and enabling informed de-
cisions on how to make the most of the faint nuclear signals to resolve
complex chemical and biological problems.
We are deeply indebted to our colleagues who contributed to this volume,
and we express special thanks to Professor Lucio Frydman for contributing
his perspective in the Foreword. We are also grateful to the editorial staff
of the Royal Society of Chemistry for their enthusiasm for this project and
their tireless efforts during editing and production. Finally, MM wishes to
acknowledge support from the Australian Research Council in establishing
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x Preface
fast acquisition methods towards the automation of protein structure

determination by NMR (FTl10100925). JCH wishes to acknowledge the
generous support of the US National Institutes of Health via the grant
P41GM111135, which enabled the establishment of NMRbox.org: National
Center for Biomolecular NMR Data Processing and Analysis. All of
the authors of computer codes for non-Fourier methods represented in

this book have generously consented to distributing their software via
NMRbox.org.
Mehdi Mobli and Jeffrey C. Hoch

Contents
Chapter 1 Polarization-enhanced Fast-pulsing Techniques 1

Bernhard Brutscher and Zsofia Solyom
1.1 Introduction 1
1.1.1 Some Basic Considerations on NMR
Sensitivity and Experimental Time 2
1.1.2 Inter-scan Delay, Longitudinal Relaxation,
and Experimental Sensitivity 3
1.2 Proton Longitudinal Relaxation Enhancement 6
1.2.1 Theoretical Background: Solomon and
Bloch–McConnell Equations 6
1.2.2 Proton LRE Using Paramagnetic Relaxation
Agents 7
1.2.3 Proton LRE from Selective Spin
Manipulation 8
1.2.4 Amide Proton LRE: What Can We Get? 11
1.2.5 LRE for Protons Other Than Amides 14
1.3 BEST: Increased Sensitivity in Reduced
Experimental Time 14
1.3.1 Properties of Band-selective Pulse Shapes 14
1.3.2 BEST-HSQC versus BEST-TROSY 18
1.3.3 BEST-optimized 13C-detected Experiments 22
1.4 SOFAST-HMQC: Fast and Sensitive 2D NMR 24
1.4.1 Ernst-angle Excitation 24

xi
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xii Contents
1.4.2SOFAST-HMQC: Different Implementations

of the Same Experiment 26
1.4.3 UltraSOFAST-HMQC 28
1.5 Conclusions 29
References 30
Chapter 2 Principles of Ultrafast NMR Spectroscopy 33

Maayan Gal
2.1 Introduction 33
2.1.1 One- and Two-dimensional FT NMR 34
2.2 Principles of UF NMR Spectroscopy 35
2.2.1 Magnetic Field Gradients 35
2.2.2 Generic Scheme of UF 2D NMR
Spectroscopy 38
2.2.3 Spatial Encoding 39
2.2.4 Decoding the Indirect Domain Information 40
2.2.5 The Direct-domain Acquisition 42
2.3 Processing UF 2D NMR Experiments 43
2.3.1 Basic Procedure 43
2.3.2 SNR Considerations in UF 2D NMR 45
2.4 Discussion 46
Acknowledgements 47
References 47
Chapter 3 Linear Prediction Extrapolation 49

Jeffrey C. Hoch, Alan S. Stern and Mark W. Maciejewski
3.1 Introduction 49
3.2 History of LP Extrapolation in NMR 50
3.2.1 Broader History of LP 51
3.3 Determining the LP Coefficients 51
3.4 Parametric LP and the Stability Requirement 52
3.5 Mirror-image LP for Signals of Known Phase 53
3.6 Application 54
3.7 Best Practices 57
Acknowledgements 58
References 58
Chapter 4 The Filter Diagonalization Method 60

A. J. Shaka and Vladimir A. Mandelshtam
4.1 Introduction 60
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Contents xiii
4.2 Theory 64
4.2.1 Solving the Harmonic Inversion Problem:
1D FDM 64
4.2.2 The Spectral Estimation Problem and
Regularized Resolvent Transform 68
4.2.3 Hybrid FDM 70

4.2.4 Multi-D Spectral Estimation and Harmonic
Inversion Problems 71
4.2.5 Spectral Estimation by Multi-D FDM 72
4.2.6 Regularization of the Multi-D FDM 76
4.3 Examples 78
4.3.1 1D NMR 78
4.3.2 2D NMR 82
4.3.3 3D NMR 86
4.3.4 4D NMR 91
4.4 Conclusions 93
Acknowledgements 93
References 94
Chapter 5 Acquisition and Post-processing of Reduced

Dimensionality NMR Experiments 96
Hamid R. Eghbalnia and John L. Markley
5.1 Introduction 96
5.2 Data Acquisition Approaches 98
5.3 Post-processing and Interpretation 100
5.4 HIFI-NMR 102
5.5 Brief Primer on Statistical Post-processing 102
5.6 HIFI-NMR Algorithm 103
5.7 Automated Projection Spectroscopy 107
5.8 Fast Maximum Likelihood Method 110
5.9 Mixture Models 111
5.10 FMLR Algorithm 112
5.11 Conclusions and Outlook 114
References 114
Chapter 6 Backprojection and Related Methods 119

Brian E. Coggins and Pei Zhou
6.1 Introduction 119

6.2 Radial Sampling and Projections 120
6.2.1 Measuring Projections: The Projection-slice
Theorem 120
6.2.2 Quadrature Detection and Projections 123
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xiv Contents
6.3 Reconstruction from Projections: Theory 125

6.3.1 A Simple Approach: The Lattice of Possible
Peak Positions 125
6.3.2 Limitations of the Lattice Analysis and
Related Reconstruction Methods 128
6.3.3 The Radon Transform and Its Inverse 130

6.3.4 The Polar Fourier Transform and the Inverse
Radon Transform 134
6.3.5 Reconstruction of Higher-dimensional
Spectra 135
6.3.6 The Point Response Function for Radial
Sampling 137
6.3.7 The Information Content and Ambiguity
of Radially Sampled Data 149
6.4 Reconstruction from Projections: Practice 151
6.4.1 The Lower-value Algorithm 151
6.4.2 Backprojection Without Filtering 153
6.4.3 The Hybrid Backprojection/Lower-value
Method 154
6.4.4 Filtered Backprojection 156
6.4.5 Other Proposed Approaches to
Reconstruction 157
6.5 Applications of Projection–Reconstruction
to Protein NMR 158
6.6 From Radial to Random 161
6.7 Conclusions 166
Acknowledgements 167
References 167
Chapter 7 CLEAN 169

Brian E. Coggins and Pei Zhou

7.2 Historical Background: The Origins of CLEAN
in Radioastronomy 170
7.3 The CLEAN Method 171
7.3.1 Notation 171
7.3.2 The Problem to be Solved 174
7.3.3 CLEAN Deconvolves Sampling Artifacts via
Decomposition 176
7.3.4 Obtaining the Decomposition into
Components 177
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Contents xv
7.3.5 The Role of the Gain Parameter 179

7.3.6 Reconstructing the Clean Spectrum 180
7.4 Mathematical Analysis of CLEAN 181
7.4.1 CLEAN and the NUS Inverse Problem 181
7.4.2 CLEAN as an Iterative Method for Solving a
System of Linear Equations 185

7.4.3 CLEAN and Compressed Sensing 193
7.5 Implementations of CLEAN in NMR 200
7.5.1 Early Uses of CLEAN in NMR 200
7.5.2 Projection–reconstruction NMR 203
7.5.3 CLEAN and Randomized Sparse Nonuniform
Sampling 203
7.6 Using CLEAN in Biomolecular NMR: Examples
of Applications 207
7.7 Conclusions 217
Acknowledgements 218
References 218
Chapter 8 Covariance NMR 220

Kirill Blinov, Gary Martin, David A. Snyder and
Antony J. Williams

8.2 Direct Covariance NMR 221
8.3 Indirect Covariance NMR 226
8.3.1 Principle 226
8.3.2 Unsymmetrical Indirect Covariance (UIC)
and Generalized Indirect Covariance (GIC)
NMR 226
8.3.3 Signal/Noise Ratio in Covariance Spectra 228
8.3.4 Artifact Detection 231
8.3.5 Applications of Indirect Covariance NMR 236
8.3.6 Optimizing Spectra for Best Application
to Covariance 239
8.3.7 Applications of Covariance Processing
in Structure Elucidation Problems 242
8.4 Related Methods 245
8.5 Conclusions and Further Directions 246
8.6 Computer-assisted Structure Elucidation (CASE)
and the Potential Influence of Covariance
Processing 247
References 249
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xvi Contents
Chapter 9 Maximum Entropy Reconstruction 252

Mehdi Mobli, Alan S. Stern and Jeffrey C. Hoch

9.2 Theory 253
9.3 Parameter Selection 257

9.4 Linearity of MaxEnt Reconstruction 258
9.5 Non-uniform Sampling 259
9.6 Random Phase Sampling 260
9.7 MaxEnt Reconstruction and Deconvolution 262
9.7.1 J-coupling 262
9.7.2 Linewidths 263
9.8 Perspective and Future Applications 263
References 265
Chapter 10 Compressed Sensing ‘1-Norm Minimisation in

Multidimensional NMR Spectroscopy 267
Mark J. Bostock, Daniel J. Holland and Daniel Nietlispach

10.2 Theory 269
10.3 Algorithms 271
10.3.1 Greedy Pursuit 273
10.3.2 Convex Relaxation Methods 275
10.3.3 Non-convex Minimisation 277
10.3.4 Other Approaches 278
10.4 Implementation and Choice of Stopping Criteria 278
10.5 Terminology 282
10.6 Current Applications 283
10.7 Applications to Higher Dimensional Spectroscopy 291
10.8 Future Perspectives 299
10.9 Conclusion 300
References 300
Subject Index 304

Published on 18 May 2017 on http://pubs.rsc.org | doi:10.1039/9781782628361-00001
CHAPTER 1
Polarization-enhanced
Fast-pulsing Techniques
BERNHARD BRUTSCHER*a,b,c AND ZSOFIA SOLYOMa,b,c
a
Institut de Biologie Structurale, Université Grenoble 1, 71 avenue des
Martyrs, 38044 Grenoble Cedex 9, France; b Commissariat à l’Energie
Atomique et aux Energies Alternatives (CEA), Grenoble, France;
c
Centre National de Recherche Scientifique (CNRS), Grenoble, France
*Email: bernhard.brutscher@ibs.fr
1.1 Introduction
The concept of multidimensional NMR spectroscopy1,2 lies at the basis of an
amazingly large number of pulse sequence experiments that have made
NMR spectroscopy a versatile tool for almost all branches of analytical
sciences. Increasing the dimensionality of the experiment provides the
required spectral resolution to distinguish individual sites in complex
molecules such as proteins and nucleic acids. It also allows encoding
information about inter-nuclear spin interactions as contributions to
resonance position, line width or intensity, providing valuable information
on the molecular structure and dynamics. However, major drawbacks
of multidimensional NMR remain its inherent low sensitivity—a direct
consequence of the weak magnetic spin interactions—as well as the long
experimental times associated with repeating the basic pulse scheme a large
number of times. Therefore, efforts are being made by scientists and NMR
spectrometer manufacturers to improve the sensitivity and speed of NMR
data acquisition. In this chapter we will describe and discuss a class of
recently developed NMR experiments, so-called fast-pulsing techniques,

1
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2 Chapter 1
which provide increased sensitivity in shorter overall experimental times.

These techniques have been developed in the context of biomolecular NMR
studies of proteins and nucleic acids, but the same ideas can also be applied
to other macromolecular systems.
1.1.1 Some Basic Considerations on NMR Sensitivity and

Experimental Time
Before discussing the particular features of fast-pulsing techniques and their
experimental implementation, we will provide a brief reminder of the main
factors that determine the experimental sensitivity and the required mini-
mal data acquisition time as these are of prime importance for designing
new experiments and for choosing the most appropriate pulse sequence for
a given application.
The signal-to-noise ratio (SNR) obtained for a particular NMR experiment
on a given NMR spectrometer depends on a number of factors that can be
summarized in the following way:
pffiffiffiffiffiffiffiffiffiffiffi.pffiffiffin1
SNR / Nexc gexc ðgdet Þ3=2 ðB0 Þ3=2 fprobe Pzss fseq Nscan 2 (1:1)
Obviously, the SNR is proportional to the number of NMR-active spins that

are available for excitation (Nexc). Increasing the sample concentration is
therefore a valid method to improve SNR. However, for biological molecules
sample concentration is often limited by molecular aggregation. SNR also
depends on the gyromagnetic ratio of the excited (gexc) as well as the detected
spin species (gdet). Note that they may be different in heteronuclear corre-
lation experiments. High-g nuclei, such as protons, are therefore preferen-
tially used as starting spin polarization sources and for NMR signal
detection. This explains why most NMR biomolecular NMR experiments rely
on proton excitation and detection. The NMR instrumentation contributes
to the achievable SNR via the magnetic field strength (B0) and the quality of
the probe used for signal detection ( fprobe). This has lead to the development
of stronger magnets, currently reaching up to 23.5 T (1 GHz 1H frequency),
and cryogenically cooled high-Q probes that yield a drastic reduction in the
electronic noise. Finally, SNR also depends on the NMR experiment to be
performed via a number of parameters: the steady state polarization PSS Z of
the excited spins, as will be discussed in more detail in the next section; an
attenuation factor fseq taking into account signal loss during the pulse se-
quence owing to spin relaxation, pulse imperfections, and limited coherence
and magnetization transfer efficiencies; the number of experimental repe-
titions Nscan; and finally the dimensionality of the experiment leading to a
O2 reduction in SNR for each indirect dimension owing to the requirement
of phase-sensitive quadrature detection. Note that the additional O2 signal
loss can be avoided by so-called sensitivity-enhanced quadrature detection
schemes.3 However, this is typically only possible in one of the indirect
dimensions, and also leads to additional relaxation-induced signal loss.
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Polarization-enhanced Fast-pulsing Techniques 3
The minimal experimental time for recording an n-dimensional (nD) data

set, with indirect time domains t1, t2 tn1, is given by the duration of the
basic pulse scheme Tscan, multiplied by the number of repetitions required
for phase cycling and time domain sampling.
(Texp)min ¼ N sampling Tscan ¼ (nPC(n1n2 nn1)2n1)Tscan

scan (1.2)
Here, nPC is the number of repetitions required to complete a given phase

cycling scheme that is used for artifact suppression and coherence transfer
pathway selection. Nowadays, with the availability of pulsed field gradients
that perform a similar task to phase cycling, nPC can often be limited to a
small number, typically 2 or 4. nk is the number of time points acquired in
the k-th time domain. For optimal performance of the experiment (in terms
of resolution and sensitivity) nk should be set to a value close to nk ¼ SWk/Dvk,
with Dvk the natural line width of the frequency edited spin species and SWk
the corresponding spectral width, resulting in typical values of nk ¼ 100–200.
The additional factor 2n1 arises from the quadrature detection scheme in
each of the n1 indirect dimensions. Consequently, using conventional
data acquisition schemes (uniform linear sampling of the grid), each addi-
tional dimension increases the experimental time by about two orders of
magnitude.
Neglecting, for the sake of simplicity, relaxation-inducedpsignal ffiffiffiffiffiffiffiffiffiffiffi loss dur-
ing the incremented time delays tk, the SNR increases with Nscan . For each
experimental setup (sample, NMR spectrometer, NMR experiment) there
exists a minimal number of scans, N SNR scan, required to achieve sufficient SNR
to distinguish the NMR signals from the noise. We can thus distinguish two
different scenarios: if N SNR sampling
scancN scan , we call this experimental situation
sensitivity-limited, while the case N SNR sampling
scan{N scan is referred to as sampling-
limited. In the sensitivity-limited regime, the basic pulse scheme has to be
repeated several times, in order to further improve SNR. Fast multidimen-
sional NMR methods, which are the topic of this book, become of interest
either for experiments in the sampling-limited regime or if the overall ex-
perimental time does become prohibitively long.
1.1.2 Inter-scan Delay, Longitudinal Relaxation, and

Experimental Sensitivity
A schematic drawing of an NMR experiment is shown in Figure 1.1a. It
consists of the pulse sequence (suite of pulses and delays) of duration tseq, a
signal detection period (tdet), and an inter-scan delay (trec) that is also called
the recycle or recovery delay. This latter delay, trec, is required to allow the
spin system, which has been perturbed by the radio frequency pulses, to
relax back toward thermodynamic equilibrium before repeating the pulse
sequence. The effective recycle delay, during which longitudinal spin relax-
ation takes place, is Trec ¼ tdet þ trec, and the total scan time, as introduced in
eqn (1.2), is given by Tseq ¼ tdet þ trec.
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4 Chapter 1
Figure 1.1 (a) Schematic representation of an NMR pulse sequence experiment,

consisting of a series of pulses and delays (tseq), a data detection
period (tdet), and a recycle delay (trec). This basic scheme needs to
be repeated Nscan times for enhancing experimental sensitivity,
phase-cycling purposes, and time incrementation in indirect dimen-
sions for multidimensional data acquisition. (b) Sensitivity curves,
calculated according to eqn (1.3), and plotted as a function of the
recycle delay Trec for different longitudinal relaxation times T1.
The duration of the pulse sequence was set to tseq ¼ 100 ms for the
calculation. (c) Dependence of the experimental sensitivity on the
duration of the pulse sequence tseq ¼ lT1. The plotted curves have
been computed for 0rlr1 in steps of 0.1 (from the top to the bottom).
The sensitivity maximum shifts from Trec/T1 ¼ 1.25 for l ¼ 0 to
Trec/T1 ¼ 1.9 for l ¼ 1.
View Online
In order to evaluate the effect of these pulse sequence parameters, and in

particular the recycle delay Trec, on the performance of the experiment in
terms of SNR, we can calculate the experimental sensitivity, defined as the
signal-to-noise ratio obtained for a fixed amount of time Texp:
pffiffiffiffiffiffiffiffiffiffiffi
Pzss Nscan 1 expðTrec = T1 Þ
ðSNRÞTexp ¼ f ðTrec Þ / pffiffiffiffiffiffiffiffiffi ¼ pffiffiffiffiffiffiffiffiffiffi (1:3)

Texp Tscan
In eqn (1.3), we have assumed that spin relaxation is mono-exponential, and

can thus be described by a single characteristic time constant T1. We would
like to emphasize here that the parameter T1 describes the time evolution of
proton polarization recovery, but can not be directly associated to a constant
with a physical meaning.
Throughout this chapter, we will refer to the dependence of the SNR on
the recycle delay as a sensitivity curve. Examples of such theoretical sensitivity
curves computed for different T1 time constants are plotted in Figure 1.1b.
The sensitivity curves show a maximum as the result of two counteracting
effects: on one hand, the steady-state spin polarization, and thus the de-
tected NMR signal, increases for longer Trec. On the other hand, when in-
creasing Trec, the number of repetitions that can be performed in a given
experimental time decreases, thus reducing SNR. For shorter relaxation time
constants T1, higher overall sensitivity is achieved with the maximum shifted
toward shorter recycle delays. As long as the sequence duration tseq is neg-
ligible with respect to T1, the optimal recycle delay and the maximal sensi-
tivity are given by:
rec D1.25 T1 for tseq{T1

T opt (1.4a)
1 1
ðSNRÞmax
Texp / pffiffiffiffiffiffiffiffi
opt
ffi / pffiffiffiffiffi (1:4b)
Trec T1
Otherwise, if tseq becomes comparable to T1, a longer Trec has to be chosen in

order to reach the highest SNR and the maximal sensitivity slightly decreases.
Sensitivity curves computed for 0otseqoT1 are plotted in Figure 1.1c.
Eqn (1.4) implies that under conditions of optimal sensitivity, the required
overall data acquisition time is proportional to T1, while the achievable
pffiffiffiffiffi
sensitivity is proportional to 1= T1 . Therefore, reducing T1 provides a con-
venient way of increasing experimental sensitivity, while at the same time
reducing the minimal required experimental time. This has motivated the
development of longitudinal relaxation enhanced (LRE) NMR techniques
that allow speeding up NMR data acquisition, as will be presented in the
following sections.
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6 Chapter 1
1.2 Proton Longitudinal Relaxation Enhancement

In this section, we will briefly discuss the spin interactions that govern
longitudinal proton spin relaxation in slowly tumbling macromolecules,
such as proteins, oligonucleotides, or polysaccharides, before discussing in
more detail the experimental LRE schemes that have been developed over
the last decade.
1.2.1 Theoretical Background: Solomon and

Bloch–McConnell Equations
The main mechanisms responsible for proton polarization buildup are the
numerous 1H–1H dipolar interactions that are present in proton-rich mole-
cules, and that are responsible for polarization transfer from one proton to
another via cross-relaxation effects. Proteins, for example, contain on aver-
age about eight protons per residue that are generally tightly packed together
within a globular fold. Formally, the time evolution of the polarization of
each proton spin in the molecule is given by the Solomon equations, a set of
coupled first-order differential equations:
0P 1
r1 j s12 s1n 0 1
0 1 0
H1z B j P C H1z H1z
B s2n C
dB C B s21 r2j CB 0 C
B H2z C B j CB H
B 2z
H2z C
C
B .. C ¼ B C B . C (1:5)
dt @ . A B . . . . .
.. C ..
B . .. .. C@ A
Hnz @ P A 0
sn1 sn2 rnj Hnz Hnz
j
where Hiz denotes the z-component of the polarization of proton i and H 0iz is
its thermal equilibrium value that, for the sake of simplicity, will be assumed
to be equal to 1 throughout this chapter. The different r and s terms stand
for auto- and cross-relaxation rate constants, respectively, with values de-
pending on the distance separating the two protons involved as well as the
global and local dynamics of the protein experienced at the sites of the
interacting protons. The auto-relaxation rate constants that are responsible
for energy exchange with the lattice (molecular motions) contain contri-
butions from dipolar interactions with all neighboring protons, and also
with neighboring hetero-atoms such as 13C and 15N in isotopic enriched
molecules. If the rotational tumbling of the molecule is slow compared
to the proton Larmor frequency (tc41/oHE109 s at high magnetic field
strengths), cross-relaxation rates become negative (sijo0), and as a con-
sequence lead to spin diffusion within the dipolar-coupled spin network. It
is worth mentioning here that the cross-relaxation rates (absolute value)
increase with the effective rotational correlation time, making spin diffusion
more efficient for larger molecules, or molecules studied at lower
temperature.
View Online
For chemically labile proton sites, e.g. amide and hydroxyl protons,
hydrogen exchange processes with the bulk water protons provide an addi-
tional relaxation source that under certain sample conditions (pH and
temperature) may even become predominant, as we will see later on. In
order to account for this exchange effect theoretically, the set of first-order
differential equations (eqn (1.5)) has to be expanded to include exchange

with the water 1H polarization, resulting in the so-called Bloch–McConnell
equations:
0 1
rW 0 0 0 0
0 1 0 1
Wz B P C Wz Wz0
B 0 r1j s12 s1n C BC
B C B C
B C B j C B H H0 C
B H1z C B C B 1z 1z C
B C B P CB C
dB C B
B H2z C B 0 s21 r2j ... s2n C B
C B H2z H2z
0 C
C
B C¼B j CB C
dt B C B CB C
B . C B CB . C
B . C B .. .. .. .. C BC B .. C
B . C B 0 . . . . C@ C
@ A B A
B C
Hnz @ P A Hnz H 0
0 sn1 sn2 rnj nz
j (1:6)
0 10 1
0 0 0 0 0 Wz
B CB C
B k kex;1 0 0 0 C B C
B ex;1 C B H1z C
B CB C
B CB C
B 0 C B H2z C
þ B kex;2 0 kex;2 0 CB C
B CB C
B . .. .. C B . C
B . CB . C
B . 0 0 . . CB . C
@ A@ A
kex;n 0 0 kex;n Hnz
with kex,i the exchange rate between proton i and water. In eqn (1.6) we have
assumed that the bulk water proton polarization Wz is not changed by
hydrogen exchange with the protein, which is a reasonable hypothesis in view
of the B105 times higher concentration of water in the NMR sample tube. The
chemical exchange rates kchem
ex depend on the local chemical environment of
the labile proton, as well as the pH and temperature. Roughly, kchemex doubles
when increasing the sample temperature by 7 1C or the pH by 0.3 units.
The apparent exchange rates kex are further modulated by the solvent acces-
sibility of the labile proton that formally is described by a protection factor
P ¼ kchem
ex /kex, varying from P ¼ 1 (no protection) to very large values, P41000
(highly protected), in the core of stable globular proteins
1.2.2 Proton LRE Using Paramagnetic Relaxation Agents

Eqn (1.6) provides the theoretical basis for the development of longitudinal-
relaxation enhancement schemes. A first strategy for accelerating longitudinal
View Online
8 Chapter 1
proton relaxation consists of the introduction of an additional auto-

relaxation mechanism, for example by adding a paramagnetic relaxation
agent to the sample. Dipolar interactions between the proton spins and the
large dipolar moment of the unpaired electron(s) in the paramagnetic
molecule enhance proton spin relaxation by adding a contribution to the
rate constants r. A list of possible paramagnetic compounds can be found in

a recent review by Hocking et al.4 We can distinguish two different types of
paramagnetic relaxation agents: (i) those acting directly on the protein nu-
clear spins and (ii) those acting primarily on the water protons. An example
of a paramagnetic chelate belonging to the first category is Ni21-DO2A.5,6 At
10 mM concentration, Ni-DO2A has been shown to reduce T1 relaxation time
constants of amide protons in proteins to about 50–200 ms.6 Of course, the
LRE effect strongly depends on the solvent accessibility of the nuclear spins,
which translates into a relatively large enhancement for surface residues,
while the effect of the paramagnetic relaxation agent is less pronounced for
residues in the interior of a protein. The use of paramagnetic relaxation
agents is therefore particularly well adapted to the NMR study of highly
flexible molecules where most of the residues are solvent exposed.6 Another
drawback of such relaxation agents is that they may cause significant line
broadening, especially in the case of specific interaction with the protein.
Ni21 has a short electronic relaxation time of T1eE1012 s, which limits the
paramagnetic induced line broadening. Another class of paramagnetic
compounds selectively enhances the 1H T1 of the bulk water. A number of
such water relaxing paramagnetic chelates have been developed as contrast
agents for magnetic resonance imaging (MRI). An example is gadodiamide
(Figure 1.2a), Gd31(DTPA-BMA), which has been commercialized as clinical
contrast agent under the name ‘‘Omniscan’’. Adding gadodiamide at 0.5 mM
concentration to an aqueous solution reduces the water T1 from a few
seconds to about 400 ms (Figure 1.2a). Gd31 complexes have been success-
fully used for relaxation enhancement in small globular proteins and IDPs,7
as well as large perdeuterated proteins.8,9
1.2.3 Proton LRE from Selective Spin Manipulation

An alternative spectroscopic method that does not require any chemical
modification of the sample is to exploit the fact that the relaxation of an
individual proton spin depends on the spin state of all other protons in the
protein and the bulk water. In particular, solving eqn (1.6) shows that
in cases where only a subset of the proton spins is of interest, a selective
excitation of these spins results in a much faster recovery than a non-selective
excitation.10,11 This is of significant practical interest to a large number of
biomolecular NMR experiments that excite and detect only a subset of pro-
ton spins, e.g. amide, aromatic, and methyl 1H in proteins, or imino, base,
and sugar 1H in nucleic acids.
In order to achieve selective excitation of only a subset of the proton spins
in a molecule, two different experimental approaches have been proposed.
View Online

Figure 1.2 Options for 1H longitudinal relaxation enhancement (LRE) techniques:

(a) a paramagnetic relaxation agent is added to the protein sample. As
an example the chemical structure of the Gd31 chelate gadodiamide,
Gd31(DTPA-BMA), is shown on the left. The effect of 0.5 mM gadodi-
amide on the water 1H longitudinal relaxation has been measured and
is shown in the right panel. The apparent T1 is reduced from 3.4
to 0.44 s at 25 1C. LRE pulse schemes based on selective 1H excitation:
(b) band-selective shaped pulses, and (c) scalar-coupling-based flip-
back scheme.
A first method (Figure 1.2b), that we will refer to as ‘‘frequency-selective’’, uses

band-selective shaped pulses to manipulate only the spins of interest, while
leaving all others unperturbed, or at least little affected by the pulse se-
quence. The obvious disadvantage of this approach is that it is limited to
proton species that are sufficiently different chemically to resonate in dis-
tinct spectral regions. Furthermore, in highly structured molecules, such as
proteins, ring-current effects may shift a particular resonance far away from
the typical chemical shift region, and as a consequence such protons may
not become excited by the selective pulses. A second ‘‘coupling-selective’’
method (Figure 1.2c) exploits the presence or absence of a scalar coupled
heteronuclear spin X (typically 15N or 13C) to achieve selective proton exci-
tation. For this purpose, broadband 1H pulses are used to excite (and re-
focus) all proton spins together. Scalar-coupling evolution during a time
interval equal to 1/JHX then creates a 1801 phase shift of protons coupled to
X, with respect to all others. A final 901 (flip-back) pulse restores the 1H
polarization for the uncoupled spins. In addition, the use of a band-selective
1801 X pulse allows even more selectivity by restricting the excitation, for
example, to 13Ca-bound protons, while protons bound to other aliphatic or
aromatic 13C are flipped back at the end of the sequence. This scheme is
View Online
10 Chapter 1
especially attractive for heteronuclear correlation experiments performed on

protein samples with partial or no isotope enrichment. It is also a good
choice for performing 1Ha excitation while leaving the water protons that
resonate in the same spectral window, close to equilibrium. A major draw-
back of such coupling-based flip-back techniques is that the efficiency of re-
storing the 1H polarization depends on the quality of the applied pulses, and
even more importantly on the transverse-relaxation induced coherence loss

during the spin evolution delay 1/JHX. This explains why, in practice, the
frequency-selective pulse excitation scheme outperforms the coupling-based
flip-back scheme whenever both approaches are feasible.
In the following, we will focus on amide 1H selective experiments of
proteins. The large majority of amide protons resonate in a narrow spectral
window (B6 to 10 ppm) that is well separated from most other (aliphatic)
protein protons and the bulk water (Figure 1.3a). Amide protons can thus be
selectively manipulated by means of appropriate shaped pulses, as discussed
in more detail later on. The effect of selective versus non-selective proton
Figure 1.3 (a) 1H spectrum of ubiquitin. The spectral regions for amide, aliphatic,
and water protons are highlighted. (b) Experimental 1H polarization
recovery curves for selected amide sites in ubiquitin,11 highlighted by
spheres on the ubiquitin structure (right panel). The solid lines are bi-
exponential fits to the data measured for selective (filled squares) and
non-selective spin inversion (filled circles).
View Online
spin inversion on the longitudinal relaxation behavior of amide protons is

illustrated in Figure 1.3b for two amide proton sites in the small protein
ubiquitin, located in a well-structured b-sheet (F4), and a highly dynamic
loop region (G10). For both amide protons, selective spin inversion leads to
significant longitudinal relaxation enhancement, while of course the exact
relaxation properties also depend on the local structure (average distance to

other protons, solvent accessibility) and dynamics (local effective tumbling
correlation time), resulting in significant differences in the apparent relax-
ation curves. Another observation is that the polarization recovery after
non-selective spin inversion is well described by a mono-exponential curve
requiring a single relaxation time constant (T1non-sel). This is generally not the
case after selective spin inversion that is best described by a
bi-exponential behavior with a fast relaxation component (T1fast) and a slow
relaxation contribution (T1slow). The magnitude of the latter is to a good
approximation equal to the relaxation time constant in the non-selective case
(T1slowET1non-sel). Although this is not a rigorous treatment, in the remainder of
this chapter we will characterize the polarization recovery under selective
conditions by a single time constant T1 ¼ T1fast that is obtained either by fitting
the first part of the inversion-recovery curve to a mono-exponential function,
or from the zero-crossing time t0 as T1 ¼ t0/ln 2 ¼ 1.44t0.
1.2.4 Amide Proton LRE: What Can We Get?

In order to quantify the achievable LRE effects for amide protons, and the
relative contributions from dipolar interactions and water exchange pro-
cesses, we have measured apparent T1 relaxation time constants for different
proteins and experimental conditions (pH and temperature). We distinguish
three different experimental scenarios depicted in Figure 1.4a: (i) amide-
proton selective spin inversion; (ii) water-flip back (wfb) spin inversion, and
(iii) non-selective spin inversion. In the first case, only amide proton spins
are inverted, while in the second case all protein protons are inverted leaving
only the water protons at equilibrium, and finally in the third case the water
protons are also inverted. The measured inversion-recovery curves of amide
1
H polarization have been fitted to a mono-exponential function, as ex-
plained in the last section, and the apparent T1 values are plotted in
Figure 1.4b–d as a function of the peptide sequence. Figure 1.4b shows the
LRE effects obtained for the small globular protein ubiquitin (tcE3 ns).
Except for a loop region (residues 9–13) and the last four C-terminal
residues, the measured relaxation time constants are quite uniform with a
non-selective T1non-selD900 ms that is reduced to T sel 1 D200 in the selective
case. The main mechanisms for this 4.5-times acceleration of longitudinal
relaxation are the dipolar interactions with neighboring non-amide protons,
while water exchange processes only marginally contribute to the LRE
effect. The observed situation is completely different for amides
located in the highly flexible protein regions, where a non-selective T1 of
up to T1non-selD2.5 s is observed, a value that approaches the T1 of
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12 Chapter 1
Figure 1.4 Residue-specific amide proton T1 time constants measured for several
proteins under different initial conditions. (a) Pulse schemes used for
spin inversion of different sets of 1H spins in inversion-recovery experi-
ments: amide 1H (HN), aliphatic 1H (HC), and water 1H (HW). The
displayed inversion-recovery block is followed by a 2D 1H–15N readout
sequence and a recycle delay of 6 s. For amide proton-selective inversion
(left panel, red bars) a REBURP pulse shape was applied with a band-
width of 4.0 ppm centered at 9.0 ppm; for water-flip-back inversion
(central panel, green bars) a 1791 inversion pulse is followed by a short
delay of 10 ms during which radiation damping brings the water back to
equilibrium; for non-selective 1H inversion (right panel, black bars) a
broad-band inversion pulse is followed by a strong pulsed field gradient
to spatially defocus residual water transverse magnetization. A low-power
magnetic field gradient is applied during the entire relaxation delay Trelax
to avoid radiation-damping effects. Apparent amide 1H T1 relaxation
time constants measured for (b) the small globular protein ubiquitin
(pH 7.5, 25 1C), and two intrinsically disordered proteins (IDPs),26 (c)
NS5A (pH 6.5, 5 1C) and (d) a-synuclein (pH 7.4, 15 1C).
View Online
water (3.4 s at 25 1C, see Figure 1.2a). Under these conditions, the
selective and wfb inversion schemes perform the same, leading to relaxation
times T1sel ¼ T1wfb ¼ 40 70 ms, clearly demonstrating that water exchange is
the main mechanism for the observed LRE effect.
Figure 1.4 also shows the measured LRE effects for two so-called in-
trinsically disordered proteins (IDPs) that have been studied under differ-
ent sample conditions: low pH (6.4) and low temperature (5 1C) for the first
one—NS5A (Figure 1.4c)—and physiological pH (7.5) and higher tem-
perature (15 1C) for the second one—a-synuclein (Figure 1.4d). IDPs have
found widespread interest in recent years in structural biology in general,
and in biomolecular NMR spectroscopy in particular.12,13 These highly
dynamic proteins or protein fragments, which are particularly abundant in
eukaryotes and viruses, have been ignored since the early days of structural
investigation of proteins. Although they have no stable structure, IDPs are
involved in many cellular signaling and regulatory processes, where
structural flexibility presents a functional advantage in terms of binding
plasticity and promiscuity.14 During recent years, NMR spectroscopy
has become the technique of choice to characterize residual structure in
IDPs and their interaction with binding partners. Owing to the low
chemical shift dispersion in the NMR spectra of IDPs, and the often-
encountered low solubility and limited lifetime of NMR samples, fast
multidimensional data acquisition techniques are of primary importance
for NMR studies of IDPs.
Interestingly, despite their high degree of internal flexibility, the LRE
effects observed in IDPs are similar to those discussed above for a globular
protein. Under conditions that do not favor solvent exchange (Figure 1.4c),
but where the local tumbling correlation times are in the slow tumbling
regime, the dipolar relaxation mechanism dominates (similar to the
structured parts of ubiquitin), resulting in a significant reduction in the
apparent average T1 time constants from T1non-selD1 s to T1selD200 ms. This
observation also indicates that a few protons at close proximity are suf-
ficient for efficient spin diffusion, and thus LRE effects. At higher pH and
temperature the solvent exchange rates increase and become the main
source of amide proton relaxation. Consequently, the relaxation behavior
of amide protons in a-synuclein (Figure 1.4d) is very similar to that ob-
served for the flexible loop and C-terminus in ubiquitin with T1non-selD2.3 s
and T1sel ¼T1wfbD60 ms. Note that this impressive LRE translates into a
sensitivity gain of up to a factor of 6 if optimal short recycle delays are
chosen, and if the pulse sequence performs perfectly in terms of selective
spin manipulation.
To conclude this section, significant LRE effects are observed for amide
protons in proteins of different size and structure, and under a variety of
experimental conditions, as a result of two complementary relaxation
mechanisms, which are dipolar interactions and solvent exchange pro-
cesses. Therefore LRE pulse schemes are expected to be of great value for all
types of amide proton-based NMR experiments.
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Maar allicht is het geoorloofd, en ook passend, tot de goden te
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En de meesten van ons waren zoolang vrij-wel in-staat onze tranen
in te houden, maar toen wij zagen dat hij dronk en gedronken had,
niet meer, maar bij mij vloeiden de tranen met geweld in stroomen,
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D weende ik niet, maar om mijn eigen lot, van welk een vriend ik
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jammerklachten los en ontstelde elk der aanwezigen, behalve
Sokrates zelven. Doch deze zeide: Wat-voor dingen doet gij nu, mijn
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vrouwen weggezonden, opdat zij met zulke dingen niet storen
E zouden. Want ik heb gehoord, dat men in heilige stilte behoort te
sterven. Doch houdt u rustig en kloek!—En wij op het hooren
hiervan, schaamden ons en lieten af van weenen. Hij wandelde eerst
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tot-tijd zijn voeten en beenen, door die te betasten, en daarop kneep
hij hem sterk in den éenen voet en vraagde of hij het voelde.
Sokrates zeide van-niet. En daarna kneep hij in de scheenbeenen,
118 en zoo omhooggaande, liet hij ons zien, dat hij langzamerhand
koud en stijf werd. Ook Sokrates zelf betastte zich en zeide, dat,
wanneer het zijn hart zoû bereiken, hij dan zoû heengaan. Reeds
begonnen ongeveer de deelen van ’t onderlijf koud te worden, toen
hij zijn gelaat onthulde—want hij had zich omhuld—, en het laatste
woord zeide, dat hij gesproken heeft: o Kritoon, wij zijn Asklepios
een haan schuldig. Geef hem dien en vergeet het niet.—Dat zal
geschieden, zeide Kritoon. Maar bedenk of gij nog iets anders te
zeggen hebt.—Op deze vraag van Kritoon antwoordde hij niet meer,
maar kort daarop kreeg hij een lichten schok, en de mensch
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Dit was het einde voor ons, o Echekrates, van onzen vriend, een
man, zooals wij zouden zeggen, van zijn tijdgenooten die wij leerden
kennen, den besten, en ook overigens den wijsten en
rechtvaardigsten.
AANTEEKENINGEN
60D. E u e n o s . Sofist en dichter, afkomstig van
het eiland Paros. Ook elders vermeldt
Platoon hem (Ap. 20B, Phaidros 267A), met
dezelfde goedmoedige ironie als hier.
89C. A r g e i e r s . Toen de Argeiers in 550 hun
zuidelijk grensgebied met de stad Thureai
aan de Lakedaimoniërs verloren, verboden
zij bij wet hun mannen lang haar, en hun
vrouwen gouden sieraden te dragen
zoolang die stad niet heroverd zoû zijn. Zie
Herodotos I 82.
I o l a o s . Neef van Herakles en diens
wagenmenner en trouwe metgezel. Toen
Herakles bij zijn strijd met de Hydra door
een reusachtige zeekrabbe werd
aangevallen, riep hij de hulp van Iolaos in.
Zie Platoons Euthydemos 297C.
90C. E u r i p o s . De om haar onstuimigheid
bekende enge zeestraat tusschen Boiotia
en het eiland Euboia op de hoogte der
steden Chalkis en Aulis.
95A. H a r m o n i a d e T h e b a a n s c h e .
Gemalin van Kadmos den Phoinikiër, den
mythischen stichter van Thebai.
97C. A n a x a g o r a s . Uit Klazomenai in Lydia.
500-428. Beroemd leerling der Ionische
natuurphilosofen. Hij vestigde zich te
Athenai en werd bevriend met den kring van
Perikles. Om zijn atheïstische stellingen
werd hij, evenals later Sokrates, van
„asebeia” beschuldigd en ontkwam alleen
door Perikles’ invloed aan de doodstraf. Hij
stierf te Lampsakos. Van zijn hoofdwerk
„Over de natuur” bestaan nog slechts
fragmenten.
108D. G l a u k o s . Waarschijnlijk wordt gedoeld op
Glaukos van Chios, den uitvinder van het
soldeeren van ijzer. Zie Herodotos I 25.
118A. Wij zijn A s k l e p i o s een haan schuldig.
Het gewone offer aan den god der
geneeskunde, wanneer men van een ziekte
is hersteld.
Colofon
Duidelijke zetfouten in de originele tekst zijn verbeterd. Wisselende spelling is
gecorrigeerd. Daarnaast is aangepast:
Pagina Origineel Aangepast

5 Apollodoras Apollodoros
14 bovenal boven-al
14 daarstraks daar-straks
16 allang al-lang
20 allang al-lang
22 ten-minst tenminste
25 voorzoover voor-zoo-ver
26 wordingsovergang wordings-overgang
26 wordingsovergangen wordings-overgangen
28 methematische mathematische
30 daarstraks daar-straks
36 ons-zelven onszelven
41 een een een
42 voorzoover voor-zoo-ver
43 zonderdat zonder dat
60 mijzelf mij-zelf
61 mijzelf mij-zelf
66 mijzelf mij-zelf
88 zoo-lang zoolang
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Textbook Fast NMR Data Acquisition Beyond The Fourier Transform 1St Edition Mehdi Mobli Ebook All Chapter PDF

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Fast NMR data acquisition beyond the

Fourier transform 1st Edition Mehdi

Music Through Fourier Space Discrete Fourier Transform

Numerical Exploration of Fourier Transform and Fourier

Modern NMR Approaches to the Structure Elucidation of

Analysis Techniques for Racecar Data Acquisition 2nd

Data Visualization with Python and JavaScript Scrape

Data Smart: Using Data Science to Transform Information

Fast Data Processing with Spark 2 Krishna Sankar

Numerical Fourier Analysis 1st Edition Gerlind Plonka

Beyond the Fourier Transform

New Developments in NMR

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Fast NMR Data Acquisition

New Developments in NMR No. 11

Print ISBN: 978-1-84973-619-0

r The Royal Society of Chemistry 2017

All rights reserved

For further information see our web site at www.rsc.org

Few branches of spectroscopy match the versatility, applicability and im-

New Developments in NMR No. 11

nor psychology’s contemporary understanding of living bodies and minds

single approach will fit best the hundreds of multidimensional experiments

NMR spectroscopy is ubiquitous in structural elucidation of synthetic

New Developments in NMR No. 11

drastically faster sampling in time. Together, methods based on nonuniform

book. Methods based on modelling the signal to obtain high resolution

fast acquisition methods towards the automation of protein structure

the authors of computer codes for non-Fourier methods represented in

Mehdi Mobli and Jeﬀrey C. Hoch

Chapter 1 Polarization-enhanced Fast-pulsing Techniques 1

New Developments in NMR No. 11

1.4.2SOFAST-HMQC: Diﬀerent Implementations

Chapter 2 Principles of Ultrafast NMR Spectroscopy 33

Chapter 3 Linear Prediction Extrapolation 49

Chapter 4 The Filter Diagonalization Method 60

4.2.3 Hybrid FDM 70

Chapter 5 Acquisition and Post-processing of Reduced

Chapter 6 Backprojection and Related Methods 119

6.1 Introduction 119

6.3 Reconstruction from Projections: Theory 125

6.3.3 The Radon Transform and Its Inverse 130

Chapter 7 CLEAN 169

7.1 Introduction 169

7.3.5 The Role of the Gain Parameter 179

System of Linear Equations 185

Chapter 8 Covariance NMR 220

8.1 Introduction 220

Chapter 9 Maximum Entropy Reconstruction 252

9.1 Introduction 252

9.3 Parameter Selection 257

Chapter 10 Compressed Sensing ‘1-Norm Minimisation in

10.1 Introduction 267

Subject Index 304

New Developments in NMR No. 11

which provide increased sensitivity in shorter overall experimental times.

1.1.1 Some Basic Considerations on NMR Sensitivity and

Obviously, the SNR is proportional to the number of NMR-active spins that

Polarization-enhanced Fast-pulsing Techniques 3

The minimal experimental time for recording an n-dimensional (nD) data

(Texp)min ¼ N sampling Tscan ¼ (nPC(n1n2 nn1)2n1)Tscan