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Book Review Molecular Modelling. Principals and Applications. By A. R. Leach

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BOOKS
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such as ourselves. There then follows a
brief outline of enzyme catalysis, with necessarily simplified views of mechanisms
by which enzymes are known to effect
catalysis, including transition-state stabilization, covalent catalysis, and acid base
catalysis. The discussion of mathematical
modeling of enzyme kinetics and inhibition introduces the fundamentals such as
the Michaelis-Menten model and the important inhibition mechanisms that a student needs to understand. The following
subsection focusses on the mechanisms of
metabolic regulation and includes transcriptional control with a specific example
of the lac operon, hormonal regulation of
glycogen biosynthesis, and allosteric regulation of aspartate transcarbamoylase.
The biochemistry of so-called ‘energy
metabolism’ processes is then discussed.
This includes a thermodynamic profile of
the phosphoric acid anhydride bond in
ATP, photosynthesis, the citric acid cycle,
glycolysis, the respiratory chain, ATP
biosynthesis, and studies of the key enzymes as components and regulatory elements in these processes. This is followed
by catabolic and anabolic metabolic processes in which carbohydrates, fats,
proteins, and nucleic acids are the key
components. Specific examples to note
are the P-degradation of fatty acids,
transamination and deamination of
amino acids, purine, pyrimidine, and porphyrin biosynthesis.
Section 4, organelles, gives a preliminary introduction to cell structure and
methods for cell fractionation, before describing in detail the functions of some of
the component organelles, including the
mitochondria, the cell membrane, the endoplasmic reticulum, and lysosomes. This
section contains a much more detailed
study of genomic function than given earlier (Section 2), with particular reference
to gene technology, DNA sequencing and
cloning, PCR, and RFLP.
Section 5, tissues and organs, forms a
major part of the book and reinforces the
utility of this atlas to the medical biochemistry student. The authors discuss
the biochemistry and, where necessary for
clarification, the relevant physiology of
most of the major organ classes in the human body, including the blood, liver, kidneys, muscle, connective tissue, and brain.
Section 6, nutrition, presents a biochemical perspective of this area and outlines
the natural sources and functions of vitamins, minerals, and trace elements in the
human body.
Section I , hormones, describes some examples of the different hormone classes
and their mechanisms of action. Specific
examples include lipophilic hormones
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0 WILEY-VCH
such as the steroids involved in reproduction and metabolic control, and their
biosynthesis and inactivation are described. Secondary messengers are also
described in this section and clear diagrams help to delineate the mechanisms of
adenylate cyclase activation and signal
transduction by G proteins.
The book ends with a number of clear
and very well constructed metabolic
charts as mentioned earlier. For students
these charts may serve to make the process of learning and memorizing these key
complex biochemical transformations
much less soul-destroying than from a
standard text.
On the whole the book serves as an excellent visual portrayal of the key biochemical processes occurring in humans
and mammals. In conjunction with other
larger and more detailed works on biochemistry, this atlas supplies the necessary
information for the student of biochemistry.
Paul Wentworth Jr., Kim D. Janda
Department of Chemistry
Scripps Research Institute and
Skaggs Institute for Chemical Biology
La Jolla, CA (USA)
Molecular Modeling. Basic Principles
and Applications. By H.-D. Holtje and
G. Folkers. VCH Verlagsgesellschaft,
Weinheim, 1996. 194 pp., hardcover
DM 198.00.-ISBN 3-527-29384-1
Molecular Modelling. Principles and
Applications. By A . R. Leach. Longman, Singapore, 1996. 595 pp.,
paperback .f 35.00.4SBN 0-58223933-8
Molecular modeling, more accurately
described as computer-aided simulation
of molecular properties, is now a widely
used method in many areas of chemistry.
When used correctly by someone with the
necessary know-how, the techniques
grouped together under this heading can
lead to a better understanding of molecular processes, and can provide knowledge
for planning experiments and for developing chemical compounds with novel properties. However, the attitudes of many scientists towards these methods are far
from realistic. At one extreme there is the
view that any chemist can easily use modeling methods, whereas at the other they
are regarded as merely games for computer freaks, and are thought to need much
further development before they can become a useful tool of chemical research.
From my own observations, anyone believing the first statement usually changes
Verlag GmbH, D-69451 Weinhelm, 1997
sooner or later to the second. Modeling
methods are of great value for the purposes mentioned above, but only in the hands
of those who know how to use them effectively. On the other hand, anyone (and
not only chemists) can produce meaningless colorful images on the computer
screen. The two books reviewed here aim
to provide their readers with the background knowledge needed to use molecular modeling techniques effectively.
Molecular Modeling. In the first book
Holtje and Folkers have set out to provide
a broadly-based practical introduction to
molecular modeling methods. Appropriately, a distinction is made between the
treatment of “small molecules” and that
of proteins, and one example of each type
is discussed.
The topics treated in the chapter on
small molecules are: methods for generating three-dimensional atomic coordinates, methods of geometrical optimization, conformational analysis, methods
for calculating molecular interaction potentials, the identification of pharmacophores, and the use of data banks. For
each of these topics the authors discuss in
detail the different approaches and the
critical steps. The main emphasis is not on
the scientific background (e.g., details of
force-field calculations), but on practical
aspects such as different minimization
techniques, the calcutation of atomic
charges and of their effects, hydrophobic
interactions, or the overlapping of molecules.
The introduction to the modeling of
proteins describes in detail methods for
predicting the structures of homologous
proteins. Each of the individual steps in
sequence alignment from predictions of
side-chain and main-chain structures, and
in the refinement of models using force
field and molecular dynamics models, is
briefly described. Methods for taking into
account solvent effects are also described,
and the authors discuss possible ways of
validating a structural model that has
been developed. This part of the book
ends with a discussion of protein properties and of protein- ligand complexes.
The only section that seems rather out of
place here is the brief description of the
principles of three-dimensional protein
structures, which can be found in any textbook of biochemistry.
Each of the above two subject areas is
illustrated by discussing an instructive example. For the small molecule case the
example chosen is the simulation of a receptor binding pocket, leading to the
identification of a pharmacophore. For
proteins the example described in detail is
the modeling of a protein-ligand com-
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Angen Chem Int Ed. Engl 1997.36,No 18
BOOKS
plex involved in antigen presentation by a
protein belonging to MHC Class I.
This book is ideally suitable for scientists or advanced students who need a
quick up-to-date overview of the methods
and capabilities oi’ molecular modeling,
and who wish to be able to evaluate alternative methods in cases where there are
several possible approaches. In most cases
the authors have deliberately limited their
treatment to brief descriptions of the various methods, leaving the reader to obtain
background information and further details from the literature references attached to each chapter. This is the only
aspect of the book that I would criticize,
since here it would have been a great advantage to also include the titles of the
papers cited. However, despite this minor
complaint I hope that the book will reach
a wide readership. It will be of great value
in helping the reader to realistically evaluate the capabilities of these methods.
Molecular Modelling. Although the title
of Leach’s book is almost identical to that
of the one reviewed above, the concept on
which it is based is quite different. Whereas the book from the VCH publishing
house has a strong practical bias with only
a brief sketch of the theory, Leach has set
out to present the theoretical background
of moIecular modeling methods.
A short introductory chapter with definitions of some important concepts is followed by one of about 100 pages containing a well written and informative, but
very theoretical, treatment of quantummechanical models. Chapter 3 then gives a
Angeu Chem
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Ed Engl 1997, 36, No 18
detailed account of empirical force-field
models for the simulation of larger molecules. Although this subject is covered in
many books on quantum-mechanical aspects, this is one of the best treatments
that I have yet seen.
Chapter 4 discusses the various energy
minimization techniques that are used in
conjunction with both quantum-mechanical and force-field methods. The author
also considers practical questions about
the applicability of the techniques. Applications of modeling methods to the simulation of molecular properties are discussed in Chapter 5. The next two
chapters are concerned with molecular
dynamics simulation methods and Monte
Carlo methods, both of which can be used
to generate large numbers of states for describing the dynamics and statistics of
molecular systems. The author discusses
the differences between the methods, and
considers the best choice for a given situation.
Chapter 8 deals with conformational
analysis, including studies involving the
molecular conformation space, molecular
fitting methods, the use of structural data
banks, and the problem of predicting conformational structures of proteins. There
are many points in this chapter where one
would have preferred to see the topics
treated in greater depth. The last two
chapters are concerned with some of the
more sophisticated applications of molecular modeling methods, such as calculations of free enthalpy, the simulation of
solvation processes and of chemical reac-
0 WILEY-VCH
Verlag GmbH, D-69451 Wemhelm, 1997
tions, and the discovery or design of new
molecules; aspects covered include drug
design, ligand design, docking, QSAR,
and lead structures.
The book is heavily biased towards theory (480 pp.) as compared with applications (about 100 pp.). Nevertheless, it
clearly brings out the variety of uses of the
methods. Each chapter ends with suggestions for further reading and a comprehensive list of references (including titles
of publications). It is a carefully written
work which is satisfying to read, and can
be recommended for everyone who wishes
to understand modeling methods. It
should also serve as a reference source to
provide essential background information
when one is using modeling software
packages in practical situations. It is not
a suitable book for gaining a quick
overview of the subject.
These two books have been written
with different aims, and both fill real gaps.
In many respects they are, in fact, complementary. Anyone with a serious intention
to work in the field of molecular modeling
should ideally use the two books in combination. On the other hand, the reader
who expects to make only occasional use
of these methods should rely on the book
by Holtje and Folkers, while reserving the
option to refer to Leach’s book or to the
original literature in doubtful cases. Both
books have the potential to become standard works.
DietmLzr Schomburg
Institut fur Biochemie
der Universitat Koln (Germany)
0570-0833/97/3618-2021 $ 1 7 SO+ SO 0
2021
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