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 Chemical Reagents for
PROTEIN
MODIFICATION
Third Edition

Copyright 2005 by CRC Press

 Chemical Reagents for
PROTEIN
MODIFICATION
Third Edition

Roger L. Lundblad

CRC PR E S S
Boca Raton London New York Washington, D.C.

Copyright 2005 by CRC Press

 1983_C00.fm Page iv Thursday, October 7, 2004 11:53 AM

Library of Congress Cataloging-in-Publication Data

Lundblad, Roger L.
Chemical reagents for protein modification / by Roger L. Lundblad.—3rd ed.
p. cm.
Includes bibliographical references and index.
ISBN 0-8493-1983-8 (alk. paper)
1. Proteins—Chemical modification. I. Title.

QP551.L883 2004
572′.6—dc22 2004051973

This book contains information obtained from authentic and highly regarded sources. Reprinted material
is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable
efforts have been made to publish reliable data and information, but the author and the publisher cannot
assume responsibility for the validity of all materials or for the consequences of their use.

Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic
or mechanical, including photocopying, microfilming, and recording, or by any information storage or
retrieval system, without prior permission in writing from the publisher.

The consent of CRC Press does not extend to copying for general distribution, for promotion, for creating
new works, or for resale. Specific permission must be obtained in writing from CRC Press for such
copying.

Direct all inquiries to CRC Press, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431.

Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are
used only for identification and explanation, without intent to infringe.

Visit the CRC Press Web site at www.crcpress.com

© 2005 by CRC Press

No claim to original U.S. Government works

International Standard Book Number 0-8493-1983-8
Library of Congress Card Number 2004051973
Printed in the United States of America 1 2 3 4 5 6 7 8 9 0
Printed on acid-free paper

Copyright 2005 by CRC Press

 1983_C00.fm Page v Thursday, October 7, 2004 11:53 AM

Preface
This material first appeared in 1983 as Chemical Reagents for Protein Modification.
The first version was prepared in collaboration with Dr. Claudia Noyes, who moved
on to greener pastures, leaving me with sole responsibility for the later versions that
appeared in 1991 and 1994. The current edition represents a major revision from
previous editions. The chapters on amino acid analysis, peptide separation by HPLC,
and amino acid sequence determination have been removed. The material on amino
acid analysis has been set as Appendix II (determination of protein concentration),
as amino acid analysis is increasingly regarded as a gold standard in the determi-
nation of protein concentration.
In the preface of the 1994 edition I stated, “While a consideration of major
biochemical journals would suggest that the use of chemical modification to study
the relationship between structure and function in proteins is no longer an active
area…” I retract this statement for the present edition with the caveat that it is
increasingly difficult to know whether chemical modification has been used in a
given study without a thorough consideration of the manuscript. This is most notable
in proteomics, wherein chemical modification is extensively used but never really
discussed. The present material will be of significant value to investigators working
in proteomics. Another area is the biochemistry of aging, wherein oxidation and the
various reactions of nitric oxide are of great importance. The study of these phe-
nomena would not be possible without considering previous work on the chemical
modification of proteins.
I hope that this book will be of value to investigators with training in different
disciplines. I strongly encourage the rigorous reporting of laboratory techniques. It
is discouraging to read an otherwise useful paper in which temperature is referred
to as room temperature, reaction time is not given, buffer details are not presented,
and so on. If investigators wish to have their work seriously considered for thera-
peutic or diagnostic development, information such as precise temperature and
reaction time is required.
Finally, I strongly encourage the careful consideration of Chapter 1 before
embarking on the design of an experiment by using chemical reagents for the
modification of proteins.

Copyright 2005 by CRC Press

 1983_C00.fm Page vii Thursday, October 7, 2004 11:53 AM

Acknowledgments
In the previous version of this material, Techniques in Protein Modification, I com-
mented that major portions of the book had been written in various airports and at
various altitudes. I am not sure whether this is a good way to write a book, and
hence the present version has been written in Chapel Hill, NC. Thus, my first
acknowledgment is to the libraries of the University of North Carolina at Chapel
Hill. The staff and facilities of the Health Sciences Library, the Kenan Library in
the Department of Chemistry, and the Brauer Library (Physics, Mathematics) were
very helpful. I acknowledge Professor Bryce Plapp of the University of Iowa for his
encouragement to the thermodynamically challenged and Professor Nicholas Price
of the University of Glasgow for guidance regarding content. Other individuals
making unique contributions include Professor William McClure of the University
of Southern California and Professors Charles Craik and Robert Fletterick of the
University of California at San Francisco. I am indebted to Professor Ralph Bradshaw
of the University of California at Irvine for his guidance in both the murky world
of proteomics and the continuing dominance of Duke basketball. Finally, I acknowl-
edge the continuing force of the fifth floor of Flexner Hall at the Rockefeller
University.

Roger L. Lundblad

Copyright 2005 by CRC Press

 1983_C00.fm Page ix Thursday, October 7, 2004 11:53 AM

Table of Contents
Chapter 1 The Site-Specific Chemical Modification of Proteins

Chapter 2 The Modification of Amino Groups

Chapter 3 The Modification of Histidine Residues

Chapter 4 The Modification of Arginine

Chapter 5 The Modification of Carboxyl Groups

Chapter 6 The Modification of Cysteine

Chapter 7 The Modification of Cystine

Appendix I: Microprocedure for the Reduction and
Carboxymethylation of Proteins
General Comments
Materials
Procedure
Notes

Chapter 8 The Modification of Methionine

Chapter 9 The Modification of Tyrosine

Chapter 10 The Chemical Modification of Tryptophan

Chapter 11 The Chemical Cleavage of Peptide Bonds

Chapter 12 The Chemical Cross-Linking of Peptide Chains

Appendix I Some Reagents Used in the Modification of Proteins

Appendix II Assay of Protein Concentration in Solution

Microplate Biuret Assay
Reagent Preparation
Standard

Copyright 2005 by CRC Press

 1983_C00.fm Page x Thursday, October 7, 2004 11:53 AM

Blank
Procedure
Comments
BCA (Bicinchoninic Acid) Assay for Protein
Reagent Preparation
Standard
Blank
Procedure
Comments
Dye-Binding Assay for Protein Using Coomassie Brilliant
Blue G-250
Reagent Preparation
Standard
Blank
Procedure
Comments
Amino Acid Analysis

Copyright 2005 by CRC Press

 1983_C00.fm Page xi Thursday, October 7, 2004 11:53 AM

Author
Dr. Roger Lundblad is a native of San Francisco, CA, and resident of Chapel Hill,
NC, where he is an independent consultant in biotechnology. He is the immediate
past editor-in-chief of Biotechnology and Applied Biochemistry and at present a
member of the editorial board. He is also an adjunct professor of pathology at the
University of North Carolina at Chapel Hill. Dr. Lundblad received his B.S. in
chemistry from Pacific Lutheran University in Tacoma, WA, and his Ph. D. degree
from the University of Washington in Seattle. After several years of post-doctoral
study at the Rockefeller Institute in New York, with Nobel laureates Stanford Moore
and William Stein, he joined the faculty of the University of North Carolina at Chapel
Hill in 1968. He rose quickly through the ranks and was promoted to professor of
pathology, biochemistry and periodontics in 1977. In 1991, he was recruited by
Baxter Healthcare as director of technology development at the Hyland Division
Facility in Hayward, CA. Dr. Lundblad moved to southern California in 1992 to
become director of science and technology development at Baxter Hyland in Duarte,
CA. During his time at Baxter, he became a member of the Senior Leadership Group
in the Baxter Technical Council and was chair of the committee on technical and
organizational knowledge. Dr. Lundblad left Baxter in 2000 to become an indepen-
dent consultant in biotechnology.
Dr. Lundblad is the author of more than 120 publications and is also the author
of best-selling books on protein chemistry. He has edited several books in the area of
biotechnology. Dr. Lundblad is recognized as an expert in the area of protein
chemistry, thrombosis and hemostasis, biotechnology manufacturing, process vali-
dation, assay validation, GLP laboratory compliance, product development, and
cGMP issues.

Copyright 2005 by CRC Press

 1983_C01.fm Page 1 Monday, October 4, 2004 11:54 AM

1 The Site-Specific
Chemical Modification
of Proteins
The advent of techniques such as site-specific mutagenesis (oligonucleotide-directed
mutagenesis) and solution chemistry approaches such as nuclear magnetic resonance
has been of great value to protein chemistry. Notwithstanding these remarkable advances
in technology, the chemical modification of proteins continues to be quite useful in
the study of proteins.1–20
Site-specific chemical modification has been very useful as a tool in proteomics.
The chemistry for the application is well known and the remarkable advances in the
use of site-specific chemical modification in proteomics are clearly a result of the
combination of mass spectrometry and data processing.21–29 The use of isotope-coded
affinity tags (ICATs) was developed by Abersold and colleagues.30–32 ICATs enabled
the relatively specific introduction of a deuterium-labeled moiety on the sulfhydryl
groups of a protein. The use of a chemically identical modifying reagent not con-
taining deuterium allows the comparison of protein expression.33 The presence of a
biotin moiety permits the isolation of modified peptides. Subsequent work has refined
this technique34–36 and reagents that target residues other than cysteine have been
developed.37–39 The development of a reagent with an acid-labile link to a resin
permits the facile purification of peptides.40 Figure 1.1 shows a general description
of the affinity purification of peptides by these techniques. A related approach uses
the incorporation of stable isotope-labeled amino acids in cell culture (SILAC).41
Other examples of site-specific chemical modification in proteomics include the
reaction of fluorogenic reagents for the modification of lysine residues, which pro-
vides high sensitivity in the analysis of proteins by two-dimensional capillary
electrophoresis42; the selective modification of thiophosphorlated peptides at low pH
with an derivative of iodoacetic acid43; and the oxidation of methionine residues
with hydrogen peroxide.44 The in situ oxidation of methionine45 was used to identify
methionine peptides in an earlier version of two-dimensional electrophoresis (diag-
onal electrophoresis).46,47 Modification of active-site residues with fluorescent
probes48,49 or biotin-containing probes49 has been reported. A related approach has
allowed the identification of protein substrates for transglutaminases, using biotiny-
lated amino- and acyl-donor probes.50 It has been possible to modify 3-nitrotyrosine
residues in complex mixtures by first reducing the protein mixture with dithiothreitol
followed by alkylation with iodoacetic acid. The nitrotyrosine residues are then
reduced to the aminotyrosine derivative with sodium dithionite and alkylated with
a sulfosuccimidyl derivative.51 The presence of a biotin tag allows the isolation of

Copyright 2005 by CRC Press

 1983_C01.fm Page 2 Monday, October 4, 2004 11:54 AM

2 Chemical Reagents for Protein Modification, Third Edition

H2
Peptide Mixture C
I Affinity Tag

1
O

H2 H2
C C
Peptide S Affinity Tag

2 Application to Affinity Matrix

H2 H2
C C
Peptide S Affinity Tag:Affinity Matrix

Affinity Purified Peptide Mixture

FIGURE 1.1 A general scheme for the purification of peptides by a combination of chemical
modification and affinity purification. Step 1 is the chemical modification of a peptide mixture
with a class-specific reagent; an iodoacetyl derivative alkylating a cysteine residue is shown
as an example. Note that the reagent has an affinity tag (e.g., biotin), which can be used for
purification of the modified peptides. Step 2 is the application to the affinity matrix; in the
case of biotin, it would be an avidin matrix. Step 3 is the elution or recovery of the bound
peptides from the affinity matrix. This could be accomplished by several approaches. First, the
modified peptide including the affinity tag could be eluted from the matrix. Second, the bond
between the affinity tag and the chemical modifier could, for example, be acid labile, in which
case the modified peptide would be removed from the affinity tag during elution. Third, the
bond formed between the chemical reagent and the modified peptide could be broken by
chemical means. For example, in the case of the chemical modification of tryptophan peptides
by sulfenyl chemistry, reduction would release the thiol-tryptophan-containing peptide.

Copyright 2005 by CRC Press

 1983_C01.fm Page 3 Monday, October 4, 2004 11:54 AM

The Site-Specific Chemical Modification of Proteins 3

the peptides containing the modified tyrosine residues. This is another example of
the application of previous work52,53 to proteomics. Clever approaches to isolate
methionine or tryptophan peptides from complex mixtures have been developed.54
Taking advantage of the selective reaction of methionine with α-keto alkyl halides
at low pH,55 methionine peptides react with a bromoacetyl function coupled to a
bead; the methionine peptides are released with 2-mercaptoethanol at pH 8.5 to 8.8.
This approach has been used to isolate methionine peptides from cell surface proteins
from a mouse monocytes cell line.56 Tryptophan peptides are isolated by reaction
with a bead containing a link to a S-sulfenyl chloride function, which reacts with
tryptophan in a manner similar to that described for the reaction with 2-nitrobenzyl-
sulfenyl chloride.57 The bound peptides are released by reduction of the disulfide
linkage between the bead and the modified tryptophan residue with 2-mercapto-
ethanol at pH 8.5 to 9.0.
The final subject in this brief discussion of the application of the site-specific
chemical modification of proteins to proteomics concerns the development of protein
microarrays. The same technologies can be used to attach proteins to biosensors for
surface plasmon resonance. The reader is directed to several recent reviews that
provide an excellent overview of protein-based microarrays.58–63 Physical absorption
to a surface or a surface modified with, for example, poly-L-lysine has been used
for many years and is the basis for ELISA-based assay systems. The trend, however,
is toward processes in which there is a chemical bond between the target protein
and the microarray surface. Most technologies involve the reaction of lysine residues
in the target protein with a suitable reactive group on the array surface. The chemistry
is similar to that used to modify lysine residues in solution.64 Attachment via other
residues is also possible by using chemistries described previously. We specifically
mention some novel approaches. Virtual mask lithography has been adapted to this
purpose by first binding streptavidin protected by a photolabile group, nitroveratryl-
oxycarbony.65 This group is removed with UV light, permitting the binding of a
biotin-labeled protein to the exposed streptavidin. One of the major issues in this
type of analysis is the correct binding of the target protein to optimize interaction.
Specific orientation of the target protein (capture agent) can be obtained by reaction
with an oxidized carbohydrate function in a Fab′ fragment.66 Although not directly
related to the chemical modification of the protein, the attachment of a hexahistidine
tail to IgA permits the correct orientation of this protein on a surface.67 The possibility
to incorporate novel amino acids in proteins that can be converted to reactive sites68
presents an opportunity to develop novel chemistries for coupling of target proteins
to surfaces.
Site-specific chemical modification has been used to produce biotherapeu-
tics.69–74 Modification of proteins and peptides with poly(ethylene glycol) (PEG;
Figure 1.2) is frequently used in the manufacture of biopharmaceuticals. There have
been numerous reviews on the use of PEG in the past several years.75–80 Successful
modification of therapeutic proteins and peptides with PEG is associated with an
extension of circulatory half-life and reduced or eliminated immunogenicity. It is
thought that these properties arise from the physical blocking of the therapeutic from
immunological surveillance and catabolic recognition. Reaction of activated PEG
molecules with proteins usually occurs at primary amino groups, but the reaction

Copyright 2005 by CRC Press

 1983_C01.fm Page 4 Monday, October 4, 2004 11:54 AM

4 Chemical Reagents for Protein Modification, Third Edition

H-(CH2CH2)n-OH

poly(ethylene)glycol

CH3-(CH2CH2)n-OH

monomethoxypoly(ethylene)glycol
PEG

O NH2 O NH
O

N +
PEG O

N-succinimidylcarbonylpoly(ethylene)glycol
N N
H H

O O

Lysine PEG-Protein

FIGURE 1.2 The modification of proteins with poly(ethylene glycol).

has been demonstrated to occur at other amino acid residues too.81 Protein engineer-
ing has been used to introduce a free cysteine residue into an immunotoxin, which
can be subsequently modified with PEG to yield a monosubstituted derivative.82
Reaction at pH values below neutrality results in monosubstitution at amino-terminal
amino groups83,84 (Table 1.1). The use of cleavable linkers has permitted the design
of PEG–protein conjugates with half-lives depending on in vivo rate of cleavage of
the linkers between the PEG moiety and the protein.85
Other protein therapeutics that use site-specific chemical modification in the
manufacturing process include various protein conjugates. Coupling of peptides and
enzymes to albumin improves circulatory half-life in glucagon-like peptide 1.86,87
Monoclonal antibody conjugates have also proved useful.88,89 The Bowman–Birk
inhibitor and an IgM antibody have been coupled to dextran via oxidation, permitting
the targeted delivery of the Bowman–Birk inhibitor to tumor cells.90 Urokinase was
coupled to pulmonary surfactant protein by using a heterobifunctional cross-linker,
S-sulfosuccinimidyl-4-(p-maleidophenyl-) butyrate.91 Cross-linking of proteins with
glutaraldehyde, polyethyleneglycol diacrylate, and formaldehyde is used to prepare
hydrogels used extensively as biomaterials.92–96 Carbamylation with potassium cyan-
ate is used in the manufacturing process of some allergens.97–100
Site-specific chemical modification is extensively used for the selective fragmen-
tation of proteins for determination of the primary structure of proteins, preparation
of large fragments for characterization by mass spectrometry, and chemical synthesis
of proteins. This includes reagents such as cyanogen bromide (CNBr) for the chemical
cleavage of specific peptide bonds, citraconic anhydride for the reversible blocking

Copyright 2005 by CRC Press

 1983_C01.fm Page 5 Monday, October 4, 2004 11:54 AM

The Site-Specific Chemical Modification of Proteins 5

TABLE 1.1
Dissociation Constants for
Nucleophiles in Proteins
Potential Nucleophile p Ka
Γ-Carboxyl (glutamic acid) 4.25
Β-Carboxyl (aspartic acid) 3.65
Α-Carboxyl (isoleucine) 2.36
Sulfhydryl (cysteine) 10.46
α-Amino (isoleucine) 9.68
Phenolic hydroxyl (tyrosine) 10.13
ε-Amino (lysine) 10.79
Imidazole (histidine) 6.00
Guanidine (arginine) 12.48

Source: Data from Mooz, E.D., In

Practical Handbook of Biochemistry
and Molecular Biology (Fasman, G.D.,
Ed.), CRC Press, Boca Raton, FL,
1989. Also see Dawson, R.M.C. et al.,
Data for Biochemical Research ,
Oxford University Press, Oxford,
1969, p. 2.

of lysine residues to restrict tryptic cleavage to arginine residues, and 1,2-cyclohex-

anedione for the reversible blocking of arginine residues to restrict tryptic cleavage
to lysine residues. CNBr has been used for top–down characterization of proteins
by mass spectrometry.101,102 CNBr cleavage of proteins yields fragments larger than
those obtained by tryptic digestion, facilitating structure assignments. In a similar
approach, modification of lysine residues with citraconic anhydride restricts tryptic
cleavage to arginine residues and yields fragments that, as with the CNBr fragments,
provide greater sequence coverage of the protein.103 CNBr fragments have been used
in the engineering of semisynthetic proteins.104 A 223-residue hybrid of Streptomyces
griseus trypsin was synthesized by native chemical ligation105 from a chemically
synthesized amino-terminal fragment and a larger carboxy-terminal fragment
obtained by CNBr cleavage. CNBr is also used for the cleavage of fusion pro-
teins.106–110
The use of specific chemical modification to study changes in the environment
has been studied over the past 30 years. The study by Kirtley and Koshland111
provided the basis for the concept of using reporter groups to study changes in the
microenvironment surrounding a site of modification. This study used 2-bromo-
acetamido-4-nitrophenol to modify a limited number of sulfhydryl groups in glycer-
aldehyde-3-phosphate dehydrogenase. The modified protein has a λmax at 390 nm
(ε = 7100 M–1 cm–1) between pH 7.0 and 7.6. The addition of the coenzyme NAD
caused a marked change in the spectral properties (decrease in absorbance at ca.
375 nm and increase in absorbance at ca. 420 nm) of the modified enzyme, which
is consistent with a change in the microenvironment around the modified residue

Copyright 2005 by CRC Press

 1983_C01.fm Page 6 Monday, October 4, 2004 11:54 AM

6 Chemical Reagents for Protein Modification, Third Edition

(increase in polarity of medium, which results in increased formation of the nitro-

phenolate ion). The reactions of 2-hydroxy-5-nitrobenzyl bromide with tryptophanyl
residues to yield the 2-hydroxy-5-nitrobenzyl derivative112 and that of tetranitro-
methane with tyrosyl residues113 to form the 3-nitrotyrosyl derivative were extensively
used to study microenvironmental changes in the modified proteins.114
Fluorescent probes have been used extensively in the study of protein confor-
mation. The chemistry used for the covalent modification of proteins is described
in detail in other chapters. The majority of studies use either lysine or cysteine as
a target residue for modification.115 The insertion of cysteine into recombinant
proteins116 via oligonucleotide-directed mutagenesis117,118 has provided opportunity
for the attachment of fluorescent probes to specific protein domains.119 Fluorescent
energy transfer (FRET) with covalently attached fluorescent probes is proving
increasingly useful in the study of protein conformation.120–123 Fluorescent probes
(dyes) have also been used to modify proteins prior to separation by two-dimensional
electrophoresis.124,125
Spin-labeled reagents (Figure 1.3) have also been useful.126 One early study used
spin-labeled derivatives of diisopropylphosphorofluoridate to study the active-site
environment of trypsin.127 Subsequent studies used various spin-labeled derivatives
(piperidinyl nitroxide, pyrrolidinyl nitroxide, and pyrrolinyl nitroxide substituent
groups) of phenylmethylsulfonyl fluoride to compare microenvironments surround-
ing the active sites in α-chymotrypsin and trypsin.128,129 These reagents have been
more recently used to study the active site of thrombin.130,131 In subsequent studies,
Nienaber and Berliner132 obtained the crystal structures of thrombin modified at the
active-site serine with two substituted pyrrolidone nitroxide derivatives, 4-(2,2,5,5-
tetramethylpyrrolidone-1-oxyl)-p-(fluorosulfonyl) benzamidine and 3-(2,2,5,5-tetra-
methylpyrrolidone-1-oxyl)-m-(fluorosulfonyl) benzamidine. The crystal structures
confirmed the earlier observations on the topography of the extended active-site
region of thrombin obtained by the previously cited electron spin resonance studies.
The preparation of spin-labeled pepsinogen has been reported.133 This study used a
N-hydroxysuccinimide ester derivative, 3-[[(2,5-dioxo-1-pyrrolidiny)oxyl] carbonyl]-
2,5,-dihydro-2,2,5,5-tetramethyl-1H-pyrrolyl-1-oxy, to modify lysyl residues in pep-
sinogen. Coupling was accomplished at pH 7.0 (0.1 M sodium phosphate) for 7 h
at 22°C, resulting in the derivatization of approximately three amino groups. Site-
directed attachment of nitroxide spin labels to inserted cysteine residues has been
used to study the conformation of S-adenosyl-methionine synthetase134 and the
mitochondrial oxoglutarate carrier.135
A spectrum of in vivo chemical modifications of proteins controls biological
activity. One group of such in vivo chemical modifications is cotranslational and
posttranslational reactions. This includes such reactions as sulfation, methylation,
and phosphorylation, which are primarily the result of enzyme-catalyzed reactions.
Note that the characterization of such reactions has benefited significantly from the
excellent previous work on the organic chemistry of proteins. A meaningful discus-
sion of cotranslational and posttranslational protein modification reactions is beyond
of the scope of this treatise. The reader is directed to several recent discussions of
this area of proteomic research.136–138

Copyright 2005 by CRC Press

 1983_C01.fm Page 7 Monday, October 4, 2004 11:54 AM

The Site-Specific Chemical Modification of Proteins 7

O
CH3
H3C

N
N
O CH3

CH3 O

3-Maleimido-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl

O
CH3
H3C
S S CH3

O
N
O CH3

CH3

1-oxyl-2,2,5,5-tetramethylpyrolidin-3-yl methyl methanethiosulfonate

CH3
H3C
O O

N
CH3 O N
O

CH3

2,2,5,5-Tetramethyl-3-pyrrolin-1-oxyl-3-carboxylic acid N-hydroxysuccinimide

FIGURE 1.3 Some useful spin-labeled reagents that have been used for site-specific modi-
fication of proteins.

In addition to cotranslational and posttranslational modifications, a number of

chemical, nonenzymatic in vivo modifications are important for the regulation of
protein function. Some of these modifications appear to be random, whereas others
appear to be specific, following the same rules for site-specific chemical modification

Copyright 2005 by CRC Press

 1983_C01.fm Page 8 Monday, October 4, 2004 11:54 AM

8 Chemical Reagents for Protein Modification, Third Edition

as discussed next. These reactions include oxidation, various reactions with nitric
oxide, and glycation.
Oxidation of proteins occurs in vivo with generally unfavorable consequences.
For example, oxidation of the active-site methionine residue in alpha-1-antitrypsin
(alpha-1-antiprotease inhibitor) results in pulmonary damage.139–141 Methionine is
quite susceptible to oxidation, first to the sulfoxide, a reversible reaction, and then
to the sulfone.142,143 There is wide spectrum of oxidizing agents, including free
radicals such as hydroxyl radical,144,145 hypochlorite,146 and organic peroxides such
as lipid peroxides in oxidative stress.147–149 Hypochlorites can be formed by the action
of myeloperoxidase and might be responsible for protein oxidation in atherosclerosis
and Alzheimer’s disease.150,151 It is also suggested that oxidative covalent modifica-
tions of proteins are signals for degradation.152
Nitric oxide is a potent physiological agent with diverse systemic effects.153–156
Peroxynitrite, formed from nitric oxide by reaction with superoxide,157–160 is a medi-
ator of some of these physiological effects of nitric oxide. The reaction of proteins
with peroxynitrite results primarily in the modification of tyrosine residues to form
3-nitrotyrosine.161–163 Peroxynitrite can also modify tryptophanyl residues164 and
oxidize methionine residues.165 Other oxidation pathways exist, resulting in carbonyl
formation and dityrosine.166–168 Carbon dioxide influences the reaction of peroxyni-
trite with proteins169,170 by forming an adduct with peroxynitrite.171 Peroxynitrite can
also react with nucleic acids,172 resulting in chain cleavage. Nitric oxide can react
directly with sulfhydryl groups on proteins, but the reactions appear to be somewhat
complicated, resulting in the formation of an S-nitroso derivative of cysteine.173,174
The reaction of proteins with nitroxyl radical is somewhat less studied.175,176
Glycation is the term used to identify the reaction of reducing sugars with
proteins. This involves the initial formation of a Schiff base followed by rearrange-
ment in the Maillard reaction,177,178 eventually resulting in advanced glycation end
products (AGEs).179 Reaction can occur at lysine and arginine residues, with resulting
cross-link formation.180,181 The glycation of proteins by methyl glyoxal has been of
specific interest.182,183
This information is provided as an overview to the current use of site-specific
chemical modification in protein chemistry. Specific information on individual mod-
ification reactions is presented in the following chapters. The material presented is
intended to be comprehensive, but the reader is also referred to other reviews on
this topic.184–199 In addition, several volumes of Methods in Enzymology200–210 are
extremely useful. The reader is also referred to Appendix I for information on the
availability of various reagents, addresses of suppliers, and a list of current journals
active in publishing the results of site-specific chemical modification studies.
An additional purpose of this chapter is to briefly introduce the concept of site-
specific chemical modification, including methods of characterizing the product of
chemical modification reactions. Site-specific chemical modification is strictly
defined as a process that yields a stoichiometrically altered protein with the quan-
titative covalent derivatization of a single, unique amino acid residue without either
modification of any other amino acid residues or conformational change. This objec-
tive is rarely obtained with most reagents, as several factors confound this goal.
First, few reagents are specific for the modification of a single functional group.

Copyright 2005 by CRC Press

 1983_C01.fm Page 9 Monday, October 4, 2004 11:54 AM

The Site- 9

Most reagents react with nucleophiles on proteins and the nucleophilic character is,
in part, dependent on the protonation state of the residue. Table 1.1 presents the acid
dissociation constants for typical amino acid functional groups. The acid dissociation
constant is dependent on the microenvironment surrounding the specific amino acid
residues, which is discussed next.
The environments of the various amino acid residues in a protein are not iden-
tical. As a result of this lack of homogeneity, a variety of surface polarities surround
the various functional groups. The physical and chemical properties of any given
functional group are strongly influenced by the nature (e.g., polarity) of the local
microenvironment. For example, consider the effect of the addition of an organic
solvent, ethyl alcohol, on the pKa of acetic acid. In 100% H2O, acetic acid has a pKa
of 4.70. Addition of 80% ethyl alcohol results in an increase of the pKa to 6.9. In
100% ethyl alcohol, the pKa of acetic acid is 10.3. This is particularly important
while considering the reactivity of nucleophilic groups such as amino groups, cys-
teine, carboxyl groups, and the phenolic hydroxyl group. When primary amines are
present in a protein, these functional groups are not reactive except in the free base
form. In other words, the proton present at neutral pH must be removed from the
ε-amino group of lysine before this functional group can function as an effective
nucleophile. Table 1.1 also gives a listing of the average pKa values for the various
functional groups present in protein. Many modification reactions take advantage of
differences in pKa values in similar chemical groups. The difference in pKa values
between an α-amino group and an ε-amino group makes it possible to selectively
modify the γ-amino group in a protein (see Chapter 2). Another example is the
selective modification of the β/γ-carboxyl groups on a protein without modification
of the α-carboxyl groups on a protein, because the protonated form of the carboxylic
acid is required for successful reaction (see Chapter 5).
Other factors that can influence the pKa of a functional group in a protein include
hydrogen binding with an adjacent functional group, the direct electrostatic effect
of the presence of a charged group in the immediate vicinity of a potential nucleo-
phile, and direct steric effects on the availability of a given functional group. An
excellent example of the effect of a neighboring group on the reaction of a specific
amino acid residue is provided by the comparison of the rates of modification of the
active-site cysteinyl residue by chloroacetic acid and chloroacetamide in papain.211,212
A rigorous evaluation of the effect of pH and ionic strength on the reaction of papain
with chloroacetic acid and chloroacetamide demonstrated the importance of a neigh-
boring imidazolium group in enhancing the rate of reaction at low pH. Similar results
had been reported earlier by Gerwin213 for the essential cysteine residues in strepto-
coccal proteinase. The essence of the experimental observations is that the plot of the
pH dependence of the second-order rate constant for the reaction with chloroacetic
acid is bell shaped, with an optimum at ca. pH 6.0, whereas that of chloroacetamide
is S shaped, approaching maximal rate of reaction at pH 10.0. Gerwin demonstrated
that the reaction of chloroacetic acid and chloroacetamide with reduced glutathione
did not demonstrate this difference in pH dependence. Other excellent examples of
the effect of neighboring functional groups are the reaction of 2,4-dinitrophenyl
acetate with a lysine residue at the active site of phosphonoacetaldehyde hydrolase,
in which the pKa of the lysine residue is decreased to 9.3 as a result of a positively

Copyright 2005 by CRC Press

 1983_C01.fm Page 10 Monday, October 4, 2004 11:54 AM

10 Chemical Reagents for Protein Modification, Third Edition

charged environment214 and the effect of remote sites on the reactivity of histidine
residues in ribonuclease A.215 Schmidt and Westheimer216 made the seminal obser-
vations on the reaction of 2,4-dinitrophenyl propionate with the active-site lysine of
acetoacetate decarboxylase, demonstrating a pKa of 5.9 for this residue. These
examples clearly demonstrate the effect of electrostatic effects on the reactivity of
amino acid residues in proteins.
Another consideration can in a sense be considered either a cause or consequence
of microenvironmental polarity. This concerns the environment immediately around
the residue modified. These are the factors that can cause a selective increase (or
decrease) in reagent concentration in the vicinity of a potentially reactive species.
The most clearly understood example of this is the process of affinity labeling.217
Another consideration is the partitioning of a reagent such as tetranitromethane
between the aqueous environment, which is polar, and the interior of the protein,
which in nonpolar. Tetranitromethane is an organic compound and can, in principle,
react equally well with exposed and buried tyrosyl residues.218
Establishing the stoichiometry of modification is a relatively straightforward
process. First, the molar quantity of modified residue is established by analysis. This
could be spectrophotometric as, for example, with trinitrophenylation of primary
amino groups, nitration of tyrosine with tetranitromethane, or alkylation of tryp-
tophan with 2-hydroxy-5-nitrobenzyl bromide, or by amino acid analysis to deter-
mine either the loss of a residue as, for example, in photooxidation of histidine and
the oxidation of the indole ring of tryptophan with N-bromosuccinimide or the
appearance of a modified residue such as with S-carboxymethylcysteine or N1-or
N3-carboxymethylhistidine. In the situation wherein spectral change or radiolabel
incorporation is used to establish stoichiometry, analysis must be performed to
determine that there is no reaction with another amino acid. For example, the extent
of oxidation of tryptophan by N-bromosuccinimide can be determined spectropho-
tometrically, but amino acid analysis or mass spectrometric analysis is required to
determine whether modification has also occurred with another amino acid such as
histidine or methionine. It is clear that the evolution of mass spectrometry from an
esoteric, specialized laboratory resource to a technique that is as common in the
protein chemistry as amino acid analysis has provided another tool for the evaluation
of protein structure after chemical modification.219–221 As a result of the availability
of mass spectrometric analysis of proteins, there is increasing use of this technology
to evaluate the chemical modification of proteins.222–230
In the case of site-specific chemical modification of a protein, it must be estab-
lished that the modification of one residue mole per mole of protein (or functional
subunit) has occurred without modification of another amino acid. (For example,
modification has occurred only with lysine and not with tyrosine.) The reaction
pattern of a given reagent with free amino acids or amino acid derivatives does not
necessarily provide the basis for reaction with such amino acid residues in a protein.
Furthermore, the reaction pattern of a given reagent with one protein cannot neces-
sarily be extrapolated to all proteins. Results of a chemical modification can be
markedly affected by reaction conditions (e.g., pH, temperature, solvent or buffer
used, and degree of illumination). Establishment of stoichiometry does not neces-
sarily mean that this modification has occurred at a unique residue (unique in terms

Copyright 2005 by CRC Press

 1983_C01.fm Page 11 Monday, October 4, 2004 11:54 AM

The Site-Specific Chemical Modification of Proteins 11

of position in the linear peptide chain, not necessarily unique with respect to reac-
tivity). It is useful if there is a change in biological activity (catalysis, substrate
binding, ion binding, etc.) occurring concomitant with the chemical modification.
Ideally, one would like to establish a direct relationship (i.e., 0.5 mol/mol of protein
with 50% activity modification; 1.0 mol/mol of protein with 100% activity modifi-
cation). More frequently, there is the situation in which there are several moles of
a given residue modified per mole of protein, but there is reason to suspect stoichio-
metric chemical modification. In some of these situations, it is possible to fractionate
the protein into uniquely modified species. The separation of carboxy-methyl-His-
12-pancreatic ribonuclease from carboxy-methyl-His-119-pancreatic ribonuclease is
a classic example of this type of situation.231 More recently, it has been possible to
separate various derivatives of lysozyme obtained from the modification of carboxyl
groups.232 Frequently, however, although there is good evidence that multiple mod-
ified species are obtained as a result of the reaction, it is not possible to separate
apparently uniquely modified species. In the reaction of tetranitromethane with
thrombin,233 apparent stoichiometry of inactivation was obtained with equivalent
modification of two separate tyrosine residues (Tyr-71 and Tyr-85 in the B chain),
and it was not possible to separate these derivatives.
Assessing stoichiometry of modification from only the functional consequences
of such modification is a far more difficult proposition. First, there must be a clear,
unambiguous signal that can be effectively measured. In a situation in which there
are clearly multiple sites of reaction that can be distinguished by analytical tech-
niques, the approach advanced by Ray and Koshland234 is useful. This analysis is
based on establishing a relationship between the rate of loss of biological activity
and the rate of modification of a single residue. A similar approach advanced by
Tsou235–237 is based on establishing a relationship between the number of residues
modified and the change in biological activity. Horiike and McCormick238 explored
the approach of relating changes in activity to extent of chemical modification. They
state that the original concepts that form the basis of this approach are sound, but
extrapolation from a plot of activity remaining vs. residues modified is not neces-
sarily sound. Such extrapolation is only valid if the nonessential residues react much
slower (rate at least 10 times slower). Given a situation wherein all residues within
a given group are equally reactive toward the reagent in question, the number of
essential residues obtained from such a plot is correct only when the total number
of residues is equal to the number of essential residues which is, in turn, equal to
1.0. However, it is important to emphasize that this approach is useful when there
is a difference in the rate of reaction of an essential residue or residues and all other
residues in that class, as is the example in the modification of histidyl residues with
diethylpyrocarbonate in lactate dehydrogenase239,240 and pyridoxamine-5′-phosphate
oxidase.241 A major advantage in relating changes in activity to a specific chemical
modification is being able to demonstrate that the reversal of modification is directly
associated with the reversal of the changes in biological activity. Demonstrating that
the effects of a specific chemical modification are reversible lends support against
the argument that such effects are a result of irreversible and nonspecific conforma-
tional change. The issue is complicated when more than one residue is modified in
the course of the chemical reaction. Whether the residues are like or unlike amino

Copyright 2005 by CRC Press

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SYMPHONIC MUSIC ***
 Stories of
SYMPHONIC MUSIC

A GUIDE TO THE MEANING OF IMPORTANT

SYMPHONIES, OVERTURES, AND
TONE-POEMS FROM BEETHOVEN
TO THE PRESENT DAY

BY
LAWRENCE GILMAN
AUTHOR OF
"PHASES OF MODERN MUSIC"
"THE MUSIC OF TO-MORROW" ETC.
 NEW YORK AND LONDON
HARPER & BROTHERS PUBLISHERS
MCMVII
Copyright, 1907, by HARPER & BROTHERS.
All rights reserved.
Published October, 1907.
 TO
E. W. G.
 CONTENTS
PAGE
PREFACE xi
THE ORCHESTRA AS POET, PAINTER, AND DRAMATIST 1
BANTOCK
TONE-POEM, "THE WITCH OF ATLAS" 11
PRELUDE, "SAPPHO" 15
BEETHOVEN
SYMPHONY NO. 3, "EROICA" 19
OVERTURE TO "CORIOLANUS" 24
SYMPHONY NO. 6, "PASTORAL" 25
OVERTURE TO "EGMONT" 27
BERLIOZ
OVERTURE TO "KING LEAR" 31
FANTASTIC SYMPHONY 34
SYMPHONY, "HAROLD IN ITALY" 36
BIZET
SUITE FROM "L'ARLÉSIENNE" 43
CHADWICK
OVERTURE, "MELPOMENE" 49
OVERTURE, "ADONAIS" 51
OVERTURE, "EUTERPE" 52
SYMPHONIC POEM, "CLEOPATRA" 53
CHARPENTIER
SUITE, "IMPRESSIONS OF ITALY" 57
CHAUSSON
SYMPHONIC POEM, "VIVIANE" 61
CONVERSE
 ROMANCE, "THE FESTIVAL OF PAN" 65
ROMANCE, "ENDYMION'S NARRATIVE" 67
TWO POEMS, "NIGHT" AND "DAY" 68
OVERTURE, "EUPHROSYNE" 70
FANTASY, "THE MYSTIC TRUMPETER" 70
DEBUSSY
PRELUDE TO "THE AFTERNOON OF A FAUN" 73
THREE NOCTURNES 75
THREE SKETCHES, "THE SEA" 77
DUKAS
"SCHERZO," "THE SORCERER'S APPRENTICE" 79
DVOŘÁK
OVERTURE, "NATURE" 85
OVERTURE, "CARNIVAL" 87
OVERTURE, "OTHELLO" 89
SYMPHONIC POEM, "THE WOOD DOVE" 91
ELGAR
VARIATIONS ("ENIGMA") 95
OVERTURE, "COCKAIGNE" 96
TWO PIECES, "DREAM CHILDREN" 98
OVERTURE, "IN THE SOUTH" 101
FRANCK
SYMPHONIC POEM, "LES ÉOLIDES" 105
SYMPHONIC POEM, "THE WILD HUNTSMAN" 106
SUITE, "PSYCHE" 108
SYMPHONIC POEM, "THE DJINNS" 113
GLAZOUNOFF
SYMPHONIC POEM, "STENKA RÂZINE" 115
SYMPHONIC PICTURE, "THE KREMLIN" 117
GOLDMARK
OVERTURE, "SAKUNTALA" 119
SYMPHONY, "RUSTIC WEDDING" 120
GRIEG
 SUITE (NO. 1), "PEER GYNT" 123
HADLEY
TONE-POEM, "SALOME" 127
HUBER
SYMPHONY NO. 2, IN E MINOR ["BÖCKLIN"] 131
D'INDY
LEGEND, "THE ENCHANTED FOREST" 137
LEGEND, "SAUGEFLEURIE" 138
VARIATIONS, "ISTAR" 139
TONE-POEM, "SUMMER DAY ON THE MOUNTAIN" 141
LISZT
SYMPHONIC POEM, "TASSO: LAMENT AND TRIUMPH" 145
SYMPHONIC POEM, "THE PRELUDES" 147
SYMPHONIC POEM, "ORPHEUS" 148
SYMPHONIC POEM, "MAZEPPA" 151
SYMPHONIC POEM, "FESTKLÄNGE" 154
SYMPHONIC POEM, "THE BATTLE OF THE HUNS" 155
SYMPHONIC POEM, "THE IDEAL" 157
"A 'FAUST' SYMPHONY" 161
"SYMPHONY AFTER DANTE'S 'DIVINA COMMEDIA'" 164
"TWO EPISODES FROM LENAU'S 'FAUST'" 173
LOEFFLER
SYMPHONIC POEM, "THE DEATH OF TINTAGILES" 177
"POEM" ["LA BONNE CHANSON"] 182
FANTASIA, "THE DEVIL'S VILLANELLE" 184
"A PAGAN POEM" 187
MAC DOWELL
SYMPHONIC POEM, "LANCELOT AND ELAINE" 191
TWO FRAGMENTS (AFTER THE "SONG OF ROLAND") 194
SUITE (NO. 2), "INDIAN" 196
MENDELSSOHN
OVERTURE, "A MIDSUMMER NIGHT'S DREAM" 199
OVERTURE, "FINGAL'S CAVE" 200
 OVERTURE, "BECALMED AT SEA AND PROSPEROUS VOYAGE" 202
OVERTURE, "THE LOVELY MELUSINA" 203
SYMPHONY NO. 3 ("SCOTCH") 206
SYMPHONY NO. 4 ("ITALIAN") 208
RAFF
SYMPHONY NO. 3, "IN THE WOODS" 213
SYMPHONY NO. 5, "LENORE" 216
RIMSKY-KORSAKOFF
SYMPHONIC POEM, "SADKO" 221
SYMPHONY, "ANTAR" 222
SUITE, "SCHEHERAZADE" 226
"A NIGHT ON MOUNT TRIGLAV" (FROM THE OPERA-BALLET
"MLADA") 229
SUITE, "CHRISTMAS EVE" 231
SAINT-SAËNS
SYMPHONIC POEM, "OMPHALE'S SPINNING-WHEEL" 235
SYMPHONIC POEM, "PHAËTON" 236
SYMPHONIC POEM, "DANCE OF DEATH" 237
SYMPHONIC POEM, "THE YOUTH OF HERCULES" 238
SCHUMANN
SYMPHONY NO. 1, IN B-FLAT MAJOR ["SPRING"] 241
OVERTURE TO "MANFRED" 243
SIBELIUS
SYMPHONIC POEM, "LEMMINKAINEN:"
"THE SWAN OF TUONELA" 248
"LEMMINKAINEN'S HOME-FARING" 249
SMETANA
SYMPHONIC CYCLE, "MY FATHERLAND:"
I. "VYSEHRAD" 251
II. "VLTAVA" 252
III. "SÁRKA" 252
IV. "FROM BOHEMIA'S FIELDS AND GROVES" 253
V. "TABOR" 253
 VI. "BLANIK" 253
SPOHR
SYMPHONY, "THE CONSECRATION OF SOUND" 255
STRAUSS
FANTASIA, "FROM ITALY" 259
TONE-POEM, "DON JUAN" 261
TONE-POEM, "MACBETH" 264
TONE-POEM, "DEATH AND TRANSFIGURATION" 266
"RONDO," "TILL EULENSPIEGEL'S MERRY PRANKS" 269
TONE-POEM, "THUS SPAKE ZARATHUSTRA" 275
VARIATIONS, "DON QUIXOTE" 285
TONE-POEM, "A HERO'S LIFE" 292
"DOMESTIC SYMPHONY" 297
TSCHAIKOWSKY
OVERTURE, "ROMEO AND JULIET" 303
FANTASIA, "THE TEMPEST" 305
FANTASIA, "FRANCESCA DA RIMINI" 308
SYMPHONY NO. 4, IN F MINOR 316
SYMPHONY, "MANFRED" 323
SYMPHONY NO. 6, "PATHETIC" 329
BALLAD, "THE VOYVODE" 335
WAGNER
"A 'FAUST' OVERTURE" 339
"A SIEGFRIED IDYL" 343
WOLF
SYMPHONIC POEM, "PENTHESILEA" 347
INDEX 353
 PREFACE
Most concert-goers have observed, at performances of modern
orchestral works of a descriptive character, the efforts of many
persons in the audience to extract from programme notes and
analyses information as to the dramatic or pictorial or poetic
meaning of the music to which they were listening. A search for
enlightenment under such conditions necessarily leads to
disappointment, since it is either pursued distractedly while the
music is actually in progress, or during the brief and unpropitious
leisure of an intermission. The design of this book is to offer in
compact and accessible form such information as will enable the
intending concert-goer to prepare himself, in advance, to listen
comprehendingly to those symphonic works of a suggestive or
illustrative nature, from Beethoven to the present day, which are
part of the standard orchestral repertoire, and such others as seem
likely to become so—to serve, in effect, as a guide to modern
orchestral programme-music. For convenience of indication, the
designation "tone poems," as used in the sub-title, is employed in its
broadest significance to characterize all modern delineative music for
orchestra in the freer forms, whether it be a symphonic poem by
Liszt, a "legend" by d'Indy, a suite by Charpentier, a "sketch" by
Debussy, or the precise thing described by Strauss as a Tondichtung.
No exclusively musical analysis of the works discussed is attempted,
since it is aimed merely to give the concert-goer such information
concerning their illustrative purpose as will enable him to place
himself in an intelligent attitude towards their performance. Nor has
the author indulged in speculative "interpretations" of any sort
regarding the poetic content of these works; he has confined himself
in every case to setting forth only such facts and clews as have been
ascertained or justifiably inferred.
An exhaustive cataloguing of modern programme-music has not
been attempted. It has been thought worth while to include only
such works of importance as the American concert-goer is likely to
find upon the programmes of symphony concerts in this country.
Thus such submerged or moribund or otherwise negligible music as
Schumann's forgotten overture, "Julius Cæsar," Berlioz's overture to
"Waverley," Rubinstein's character-pictures, "Faust" and "Ivan IV.,"
Liszt's "Hamlet," Beethoven's "King Stephen" and "Battle of Vittoria,"
have been permitted to remain unexpounded. [1]
A book such as this must necessarily be largely of the nature of a
compilation, since, in the case of the older works in the concert-
repertoire, it must make use of information already obtained and
recorded. It is believed, however, that it may supply a want hitherto
unfulfilled in that, particularly, it assembles in convenient shape
information concerning important contemporary works which exists,
at present, only in a scattered and more or less unavailable
condition.
In justification of its purpose, the author may be permitted to say
that he considers it absurd and illogical that the concert-goer should,
as some assert, be asked to listen to a piece of descriptive music in
ignorance of its literary or pictorial or dramatic basis. He heartily
agrees with Mr. Ernest Newman, who has written with unsurpassed
acumen and force concerning programme-music and its principles,
when he asserts that "if the poem or the picture was necessary to
the composer's imagination, it is necessary to mine; if it is not
necessary to either of us, he has no right to affix the title of it to his
work; ... if melody, harmony, and development are all shaped and
directed by certain pictures in the musician's mind, we get no further
than the mere outside of the music unless we are familiar with those
pictures." A title, it is true, is sometimes sufficient as a spur to the
hearer's imagination—as in the case, for example, of such broadly
impressionistic music as Claude Debussy's "The Sea," the various
movements of which bear these subsidiary titles: "From Dawn till
Noon on the Sea"; "Frolics of Waves"; "Dialogue of the Wind and the
Sea." But what would the hearer, unacquainted with the subject
which provoked it, make of Debussy's "Prelude to 'The Afternoon of
a Faun,'" did not the appended sub-title—"Eclogue of S. Mallarmé"—
direct him to the source of the composer's inspiration, the fantastic
and singular poem of the French symbolist? Even in the case of
descriptive music based upon an exceedingly familiar subject, the
title alone may be insufficient. In the case, for instance, of Edward
MacDowell's symphonic poem, "Lancelot and Elaine," the composer
offers his listener merely the title. He has said, indeed, that he
"never would have insisted that this symphonic poem need mean
'Lancelot and Elaine' to every one." Yet if he intended this music, as
it is known that he did, to describe certain definite and particular
incidents in the story of Lancelot and the Maid of Astolat—as the
tournament, Lancelot's downfall, his interview with Guinevere, the
passing of the funeral barge—it obviously could not, without a
sacrifice of psychological and dramatic consistency, coincide with any
other sequence of happenings which the uninstructed listener might
choose to substitute. To tell the hearer that he is at liberty to
interpret a piece of avowed and detailed descriptive music according
to any "programme" which may happen to occur to him, is, in
principle, precisely like playing for him on the piano a new and
unknown song, and telling him that he may fit to it any words he
chooses.
It cannot be too positively insisted upon that, as Mr. Newman has
pointedly observed, a piece of eloquent delineative music cannot be
equally understood and appreciated by the man who knows and the
man who does not know its programme. Mr. Newman concedes, of
course, the fact that such a work as Tschaikowsky's overture,
"Romeo and Juliet," would undoubtedly "give intense pleasure to any
one who listened to it as a piece of music, pure and simple." "But I
deny," he continues, "that this hearer would receive as much
pleasure from the work as I do. He might think the passage for
muted strings, for example, extremely beautiful, but he would not
get from it such delight as I, who not only feel all the musical
loveliness of the melody and the harmonies and the tone color, but
see the lovers on the balcony and breathe the very atmosphere of
Shakespeare's scene. I am richer than my fellow by two or three
emotions in a case of this kind. My nature is stirred on two or three
sides instead of only one. I would go further and say that not only
does the auditor I have supposed get less pleasure from the work
than I, but he really does not hear Tschaikowsky's work at all. If the
musician writes music to a play and invents phrases to symbolize the
characters and to picture the events of the play, we are simply not
listening to his work at all if we listen to it in the ignorance of his
poetical scheme. We may hear the music, but it is not the music he
meant us to hear"—which is simply a more telling and vivid
statement of a truth which Berlioz enunciated more than three score
and ten years ago in a prefatory note to his Symphonie fantastique:
"The plan of an instrumental drama, being without words, requires
to be explained beforehand. The programme (which is indispensable
to the perfect comprehension of the dramatic plan of the work)
ought therefore to be considered in the light of the spoken text of an
opera, serving to ... indicate the character and expression."
It should be said, in conclusion, that these elucidations—if they may
hopefully be regarded as such—are addressed, not to the
professional student of music, but to the intelligent concert-goer
who desires to listen understandingly, and with adequate
appreciation, to those works which are intended not merely to
appeal to his perception of beautiful sound and beautiful form, but
which set before him, for the education of his heart or the delight of
his spirit, some notable and intense impression of the human drama
or the visible world.

The writer is indebted for the information accumulated in the

following pages to so many sources—biographies, autobiographies,
scores in print and in manuscript, and enlightenment personally and
most helpfully supplied by the composers of various contemporary
works—that he finds it difficult to avow them with adequate
particularity. He has consulted (to name but a few such authorities)
Riemann's Musik-Lexikon, the "Oxford History of Music," Apthorp and
Champlin's "Cyclopedia of Music and Musicians," Fétis' Biographie
Universelle des Musiciens, Grove's "Dictionary of Music and
Musicians," Schumann's "Music and Musicians," Wagner's Prose
Works, and—for records and details not generally accessible—the
exceedingly valuable programme-notes prepared for the concerts of
the Boston Symphony Orchestra, during the last six years, by Mr.
Philip Hale, and, before him, by Mr. W. F. Apthorp.
L. G.
DIXVILLE NOTCH, NEW HAMPSHIRE, SEPTEMBER, 1907.
 FOOTNOTES:

[1] Opera-overtures do not, of course, come within the scope of a

book designed expressly to serve as a guide to music written for
the concert-room. Hence, even works that are either frequently or
always played apart from their intended operatic setting—as the
several "Leonora" overtures of Beethoven, and the "Francs-Juges"
and "Benvenuto Cellini" overtures of Berlioz—are not included.
 STORIES OF
SYMPHONIC MUSIC
 THE ORCHESTRA AS POET, PAINTER,
AND DRAMATIST
"How can an orchestra, without the aid of voices or pantomime or
scenery, tell the story of Don Quixote, paint a picture of the sea, or
describe the visions of a dying man?" asks an intelligent but
somewhat puzzled layman. "I have always thought of instrumental
music," he goes on to say, "as the art of arranging tones according
to more or less binding laws of design and effect; and yet I hear
constant talk nowadays of the 'expressive capacity' of music, its
ability to paint pictures, tell stories, enact dramas. What, briefly, is
meant by the 'expressive (or pictorial or descriptive) capacity' of
music?" Perhaps it may be possible to tell him—"briefly," as he
requests.
Music in the old days—the days before Beethoven, let us say—was,
outside of the church and the opera-house, primarily an art of pure
design. The musician of those days was concerned mainly with the
arrangement of tones according to certain well-defined rules and
conventions, to the end of producing a euphonious and beautiful
pattern of sound. The symphonies of Mozart, the early symphonies
of Beethoven, had no other aim than to be beautiful. Music was
then, as has been aptly said, a species of "sensuous mathematics."
The musician who, in the year 1797, set out to compose a
symphony, proceeded according to very definite rules. He must
invent what was called a "first theme," usually rather vigorous and
assertive in character, and a "second theme," of contrasting
character—usually of a gentler and more feminine quality. These
themes were then developed at length—presented in different keys,
altered as to rhythm, harmony, and instrumentation, in whatever
manner was made possible by the composer's skill and the fertility of
his invention. Finally, the two themes were recalled in their original
state, and the first movement of the symphony was at an end. The
composer had accomplished a complete musical organism in what
was called, among his craft, "sonata form." He might then proceed
with the other movements of his symphony, which must also be
constructed according to certain specific laws. Always he must
proceed according to rule. His "second theme," for example, must be
sounded in a key which bore a hard-and-fast relationship to the key
of his "first theme"; and if his symphony began, let us say, in F
major, it must end in F major, or in some closely related key. It
would never for a moment have occurred to him—this excellent
eighteenth-century music-maker—to begin a serious composition in
F major and end it, say, in C-sharp minor: that would have seemed
an aberration of the most preposterous kind.
Our eighteenth-century instrumental composer, then, was a builder
of tonal edifices of a very plain and solid kind, which must be
proportioned and fashioned strictly according to rule. Moreover, his
constructive material, so to speak, was of the sparest. His range of
harmony was extremely small, his melodic patterns were simple in
outline and of limited expressiveness, his rhythms were square-cut
and obvious, his orchestral technique of the most meagre order.
There were, it is true, composers prior to the nineteenth century
who wrote a crude kind of orchestral programme-music [2]— music
which aimed to describe scenes and events, to picture aspects of
nature and definite states of mind. Karl von Dittersdorf (1739-1799)
composed a number of symphonies descriptive of Ovid's
"Metamorphoses"—"The Downfall of Phaëton," "Acteon's
Transformation into a Deer," "Andromeda's Rescue by Perseus,"
"Phineus with his Friends in the Mountains." Justin Heinrich Knecht
(1752-1817) anticipated certain features of the "Pastoral" symphony
in his "Tableau musical de la nature," composed when Beethoven
was fourteen years old; and Haydn gave to certain of his multiple
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