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 Preface

Computational approaches to medicinal chemical problems have developed rapidly

over the last 40 years or so. In the late 1950s and early 1960s, gigantic mainframe
computers were used to perform simple HMO (Huckel molecular orbital) and PPP
(Pariser-Parr-Pople) calculations on aromatic compounds such as substituted ben-
zenes, naphthalenes, anthracenes, etc., to explain their UV spectral properties. In the
early 1960s, stand-alone programs became available to simulate NMR spectra. With
the advent of Hansch-type analysis of structure-activity relationships (SAR), com-
puters were used to solve multiple regression equations. In 1963 the Quantum Chem-
istry Program Exchange (QCPE) started distribution of programs such as Extended
Huckel Theory (EHT) and early versions of Complete Neglect of Differential Overlap
(CNDO), which to the delight of theoretical chemists eventually made it possible to
perform conformational analyses on nonaromatic molecules. However scientifically
exciting, all these computations involved quite some expertise in mastering the
computer’s operating system as well as manual labor punching cards and hauling
boxes of punched cards to and from the mainframe computer center. Of greater
concern, however, was the fact that real-life molecules such as those routinely
synthesized by medicinal chemists were most often too big to be treated theoretically
using the computers of those days. This resulted in a situation in which the
contribution of a theoretical chemist was, at best, politely tolerated but in general
considered irrelevant to the work of a classically trained medicinal chemist.
All this changed, although slowly, in the 1970s, with improvements in the speed,
manageability, and availability of computer technology. A considerable impediment
in the late 1970s and early 1980s was the lack of proper visualization of the theoretical
results. Indeed, it was discouraging to discuss theoretical results with a suspicious
chemist on the basis of pages and pages of computer output. This obstacle was
dramatically removed with the advent of graphics computers able to depict HOMOs,
LUMOs, MEPs (molecular electrostatic potential), dipole moment vectors, etc,
superimposed on a 3D representation of the molecule(s) of interest. By the early
1990s graphics workstations linked to multiprocessor machines were powerful enough
to perform reliable calculations on real-life molecules in a time frame sufficiently small
to keep the interest of the medicinal chemist alive and to show the results in an
understandable and appealing way.
Copyright © 2004 Taylor & Francis Group LLC
 iv Preface

Nowadays, one can safely state that the computational chemist has become a
respectable member of a drug (ligand) design team, standing on an equal footing with
the synthetic chemists, pharmacologists, and others at the beginning of the long and
arduous path of ligand creation aimed toward bringing a medicine to the market.
The title of this book refers to two topics, namely, Computational Medicinal
Chemistry and Drug Design. It unites these topics by giving an overview of the main
methods at the disposal of the computational chemist and to highlight some
applications of these methods in drug design. Although drug and ligand appear to
be synonymous in this volume, they most definitely are not. Notwithstanding ‘‘drug
design’’ in the title, this volume essentially deals with methods that can be applied to
molecules that may possibly become drugs. Whether, when, and how a molecule may
acquire the status of a drug or a medicine is investigated and decided by, among others,
toxicologists, pharmacists, and clinicians and is therefore explicitly outside the scope
of this volume.
Similarly, a choice had to be made regarding the topics covered in this volume.
For example, molecular dynamics (MD) based free-energy changes in solution calcu-
lations are not treated, because these are not yet a day-to-day practice in actual ligand
design due to the very high computational demands for the long MD simulations
required.
This book starts with seven chapters devoted to methods for the computation of
molecular structure: molecular mechanics, semiempirical methods, wave function–
based quantum chemistry, density-functional theory methods, hybrid methods, an
assessment of the accuracy and applicability of these methods, and finally 3D structure
generation and conformational analysis.
In the next chapters, one or several of those formalisms are used to describe some
aspects of molecular behavior toward other molecules in terms of properties such as
electrostatic potential, nonbonded interactions, behavior in solvents, reactivity and
behavior during interaction with other molecules, and finally similarity on the basis of
nonquantum and quantum properties.
Before addressing some aspects of, broadly speaking, ligand-receptor interac-
tions, a critical evaluation of protein structure determination was felt in order. This is
then followed by accounts of docking and scoring, pharmacophore identification 3D
searching, substructure searching, and molecular descriptors.
The following chapters address 2D and 3D models using classical molecular and
quantum-based descriptors and models derived from data mining techniques as well as
library design.
Given the increasing demand for enantiomerically pure drugs, vibrational
circular dichroism (VCD) will become a standard technique in the medicinal chemical
laboratory. The VCD chapter illustrates the use of high-level quantum chemical
calculations and conformational analysis discussed in previous chapters. Similarly, the
chapter on neuraminidase highlights the combined use of protein crystallography,
ligand receptor interaction theory, and computational methods. Finally, this volume
ends with a concise glossary.
Thanks are due to Anita Lekhwani, who initially suggested this project, and to
Lila Harris, who helped in realizing the project. Each individual chapter was reviewed
by at least three editors. During monthly editorial meetings reviews were critically
compared.

Copyright © 2004 Taylor & Francis Group LLC

 Contents

Preface
Contributors

1. Molecular Mechanics and Comparison of Force Fields

Tommy Liljefors, Klaus Gundertofte, Per-Ola Norrby, and Ingrid
Pettersson

2. Semiempirical Methods
Thomas Bredow

3. Wave Function–Based Quantum Chemistry

Trygve Helgaker, Poul Jørgensen, Jeppe Olsen, and Wim Klopper

4. Density-Functional Theory
Paul W. Ayers and Weitao Yang

5. Hybrid Quantum Mechanical/Molecular Mechanical Methods

Jean-Louis Rivail

6. Accuracy and Applicability of Quantum Chemical Methods in

Computational Medicinal Chemistry
Christopher J. Barden and Henry F. Schaefer III

7. 3D Structure Generation and Conformational Searching

Jens Sadowski, Christof H. Schwab, and Johann Gasteiger

8. Molecular Electrostatic Potentials

Peter Politzer and Jane S. Murray

9. Nonbonded Interactions
Steve Scheiner
Copyright © 2004 Taylor & Francis Group LLC
 viii Contents

10. Solvent Simulation

Peter L. Cummins, Andrey A. Bliznyuk, and Jill E. Gready

11. Reactivity Descriptors

P. K. Chattaraj, S. Nath, and B. Maiti

12. Transition States and Transition Structures

Orlando Acevedo and Jeffrey D. Evanseck

13. Molecular Similarity, Quantum Topology, and Shape

Paul G. Mezey

14. Quantum Similarity and Quantitative Structure–Activity

Relationships
Ramon Carbó-Dorca and Xavier Girone´s

15. Protein Structures: What Good Is Beauty If It Cannot

Be Seen?
Sander B. Nabuurs, Chris A. E. M. Spronk, Elmar Krieger, Rob
W. W. Hooft, and Gert Vriend

16. Docking and Scoring

Ingo Muegge and Istvan Enyedy

17. Pharmacophore Discovery: A Critical Review

John H. Van Drie

18. Use of 3D Pharmacophore Models in 3D Database Searching

Re´my D. Hoffmann, Sonja Meddeb, and Thierry Langer

19. Substructure and Maximal Common Substructure Searching

Lingran Chen

20. Molecular Descriptors

Geoff M. Downs

21. 2D QSAR Models: Hansch and Free–Wilson Analyses

Hugo Kubinyi

22. 3D QSAR Modeling in Drug Design

Tudor I. Oprea

23. Computational Aspects of Library Design and Combinatorial

Chemistry
Valerie J. Gillet

24. Quantum-Chemical Descriptors in QSAR

Mati Karelson
Copyright © 2004 Taylor & Francis Group LLC
 25. Data Mining Applications in Drug Discovery
Michael F. M. Engels and Theo H. Reijmers

26. Vibrational Circular Dichroism Spectroscopy: A New Tool for

the Sterochemical Characterization of Chiral Molecules
Philip J. Stephens

27. Sialidases: Targets for Rational Drug Design

Jeffrey C. Dyason, Jennifer C. Wilson, and Mark von Itzstein

Glossary Ed E. Moret and Jan P. Tollenaere

Copyright © 2004 Taylor & Francis Group LLC

 Contributors

Orlando Acevedo Center for Computational Studies and Department of Chemistry

and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania, U.S.A.

Paul W. Ayers Department of Chemistry, McMaster University, Hamilton,

Ontario, Canada

Christopher J. Barden Department of Chemistry, Dalhousie University, Halifax,

Nova Scotia, Canada

John M. Barnard Barnard Chemical Information Ltd., Stannington, Sheffield, S.

Yorks, United Kingdom

Andrey A. Bliznynk ANU Supercomputer Facility, Australian National University,

Canberra, Australian Capital Territory, Australia

Thomas Bredow Theoretical Chemistry, University of Hannover, Hannover, Ger-

many

Ramon Carbó-Dorca Institute of Computational Chemistry, University of Girona,

Campus Montilivi, Catalonia, Spain

P. K. Chattaraj Department of Chemistry, Indian Institute of Technology, Khar-

agpur, India

Lingran Chen MDL Information Systems, Inc., San Leandro, California, U.S.A.

Peter L. Cummins Division of Molecular Bioscience, John Curtin School of Medical

Research, Australian National University, Canberra, Australian Capital Territory,
Australia

Geoff M. Downs Barnard Chemical Information Ltd., Stannington, Sheffield,

United Kingdom
Copyright © 2004 Taylor & Francis Group LLC
 xii Contributors

Jeffrey C. Dyason Griffith University (Gold Coast), Bundall, Queensland, Australia

Michael F. M. Engels Johnson & Johnson Pharmaceutical Research and Develop-

ment, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium

Istvan Enyedy Bayer Research Center, West Haven, Connecticut, U.S.A.

Jeffrey D. Evanseck Department of Chemistry and Biochemistry, Duquesne Uni-

versity, Pittsburgh, Pennsylvania, U.S.A.

Johann Gasteiger Computer-Chemie-Centrum, Institute for Organic Chemistry,

Erlangen-Nuernberg University, Erlangen, Germany

Valerie J. Gillet Department of Information Studies, University of Sheffield,

Sheffield, United Kingdom

Xavier Gironés Institute of Computational Chemistry, University of Girona, Cam-

pus Montilivi, Catalonia, Spain

Jill E. Gready Division of Molecular Bioscience, John Curtin School of Medical

Research, Australian National University, Canberra, Australian Capital Territory,
Australia

Klaus Gundertofte Department of Computational Chemistry, H. Lundbeck A/S

Copenhagen-Valby, Denmark

Trygve Helgaker Department of Chemistry, University of Oslo, Oslo, Norway

Rémy D. Hoffmann Accelrys SARL, Parc Club Orsay Université, Orsay, France

Rob W. W. Hooft Bruker Nonius BV, Delft, The Netherlands

Mark von Itzstein Institute for Glycomics, Griffith University (Gold Coast Campus),
Queensland, Australia

Poul Jørgensen Department of Chemistry, University of Aarhus, Aarhus, Denmark

Mati Karelson Centre of Strategic Competence, University of Tartu, Tartu, Estonia

Wim Klopper Institute of Physical Chemistry, University of Karlsruhe (TH), Karls-

ruhe, Germany

Elmar Krieger Centre for Molecular and Biomolecular Informatics, University of

Nijmegen, Nijmegen, The Netherlands

Hugo Kubinyi Molecular Modelling and Combinatorial Chemistry, BASF AG,

Ludwigshafen, Germany (retired)
Copyright © 2004 Taylor & Francis Group LLC
 Thierry Langer Department of Pharmaceutical Chemistry, University of Innsbruck,
Innsbruck, Austria

Tommy Liljefors Department of Medicinal Chemistry, The Danish University of

Pharmaceutical Sciences, Copenhagen, Denmark

B. Maiti Department of Chemistry, Indian Institute of Technology, Kharagpur,

India

Sonja Meddeb Accelrys SARL, Parc Club Orsay Université, Orsay, France

Paul G. Mezey Scientific Modeling and Simulation Laboratory, Memorial Univer-

sity of Newfoundland, St. John’s, Newfoundland, Canada

Ed E. Moret Department of Medicinal Chemistry, Utrecht Institute for Pharma-

ceutical Sciences, Utrecht University, Utrecht, The Netherlands

Ingo Muegge Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut,

U.S.A.

Jane S. Murray Department of Chemistry, University of New Orleans, New

Orleans, Louisiana, U.S.A.

Sander B. Nabuurs Centre for Molecular and Biomolecular Informatics, University

of Nijmegen, Nijmegen, The Netherlands

S. Nath Chemistry Department, Indian Institute of Technology, Kharagpur, India

Per-Ola Norrby Department of Chemistry, Technical University of Denmark,

Lyngby, Denmark

Jeppe Olsen Department of Chemistry, University of Aarhus, Aarhus, Denmark

Tudor I. Oprea EST Chemical Computing, AstraZeneca R&D Mölndal, Mölndal,

Sweden

Ingrid Pettersson Novo Nordisk A/S, Måløv, Denmark

Peter Politzer Department of Chemistry, University of New Orleans, New Orleans,

Louisiana, U.S.A.

Theo H. Reijmers Johnson & Johnson Pharmaceutical Research and Development,

A Division of Janssen Pharmaceutica N.V., Beerse, Belgium

Jean-Louis Rivail Groupe de Chimie théorique, ‘‘Structure et Réactivité des Sys-

tèmes Moléculaires Complexes,’’ Henri Poincaré University, Nancy-Vandoeuvre,
France
Copyright © 2004 Taylor & Francis Group LLC
 xiv Contributors

Jens Sadowski Structural Chemistry Laboratory, AstraZeneca R&D Mölndal,

Mölndal, Sweden

Henry F. Schaefer III Center for Computational Quantum Chemistry, University of

Georgia, Athens, Georgia, U.S.A.

Steve Scheiner Department of Chemistry and Biochemistry, Utah State University,

Logan, Utah, U.S.A.

Christof H. Schwab Molecular Networks GmBH, Erlangen, Germany

Chris A. E. M. Spronk Centre for Molecular and Biomolecular Informatics, Uni-

versity of Nijmegen, Nijmegen, The Netherlands

Philip J. Stephens Department of Chemistry, University of Southern California, Los

Angeles, California, U.S.A.

Jan P. Tollenaere Department of Medicinal Chemistry, Utrecht Institute for Phar-

maceutical Sciences, Utrecht University, Utrecht, The Netherlands

John H. Van Drie Vertex Pharmaceuticals, Cambridge, Massachusetts, U.S.A.

Gert Vriend Centre for Molecular and Biomolecular Informatics, University of

Nijmegen, Nijmegen, The Netherlands

Jennifer C. Wilson Griffith University (Gold Coast), Bundall, Queensland, Australia

Weitao Yang Department of Chemistry, Duke University, Durham, North Caro-

lina, U.S.A.

Copyright © 2004 Taylor & Francis Group LLC

 1
Molecular Mechanics and Comparison
of Force Fields

TOMMY LILJEFORS
The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark
KLAUS GUNDERTOFTE
H. Lundbeck A/S, Copenhagen-Valby, Denmark
PER-OLA NORRBY
Technical University of Denmark, Lyngby, Denmark
INGRID PETTERSSON
Novo Nordisk A/S, Måløv, Denmark

1. INTRODUCTION
Molecular mechanics (force field) calculation is the most commonly used type of cal-
culation in computational medicinal chemistry, and a large number of different force
fields have been developed over the years. The results of a molecular mechanics (MM)
calculation are highly dependent on the functional forms of the potential energy
functions of the force field and of the quality of their parameterization. Thus in order
to obtain reliable computational results it is crucial that the merits and limitations
of the various available force fields are taken into account. In this chapter, the basic
principles of force-field calculations are reviewed, and a comparison of calculated and
experimental conformational energies for a wide range of commonly used force fields
is presented. As quantum mechanical (QM) methods have undergone a rapid develop-
ment in the last decade, we have also undertaken a comparison of these force fields
with some commonly employed QM methods. The chapter also includes a review
of force fields with respect to their abilities to calculate intermolecular interactions.
Copyright © 2004 Taylor & Francis Group LLC
 2 Liljefors et al.

Finally, as solvent effects play an important role in computational medicinal chem-

istry, a discussion of force-field calculations including solvation is also included in
this chapter.

2. BASIC PRINCIPLES OF MOLECULAR MECHANICS

Empirical force-field methodology is based on classical mechanics and on the
fundamental assumption that the total ‘‘steric’’ energy of a structure can be expressed
as a sum of contributions from many interaction types [1–3]. Another important
assumption is that the force field and its parameters, which have been determined from
a set of molecules, are transferable to other molecules.
Molecular mechanics methods are several orders of magnitude faster than QM
methods, and for problems where MM methods are well defined, the accuracy may be
as good as or better than QM calculations at a relatively high level (see Sec. 4). The
main drawback of MM is that the method and the quality of the calculations are
extremely dependent on empirical parameters. Such parameters are generally deter-
mined by experimental studies or high-level ab initio calculations, and the parameter-
ization is often based on a small number of model systems.

2.1. Atom Types, Bonds, and Angles

The fundamental unit of most force fields is the atom type, determining what
parameters to apply for all interactions involving the same constituent atom types.
The various interaction types include bond lengths, angles, distances, etc. (see Fig. 1).
In theory, every combination of atom types needs to be specifically parameterized. In
practice, however, only the relevant combinations of these will ever be determined. For

Figure 1 Definition of basic parameters in force fields. Bond lengths (l ), angles (h), torsion
angles (x), and nonbonded distances (r) are exemplified in n-propanol.
Copyright © 2004 Taylor & Francis Group LLC
 example, force fields with a carbonyl oxygen atom type will include bonds from this to
carbon, but rarely to anything else. Thus the number of bond types in most force fields
is only a few times higher than the number of atom types. In most force fields the
parameters are further differentiated, based on the particular structural surroundings
such as bond orders or the like.
Each bond in a structure will contribute a stretch term to the total energy. Bonds
are normally described as harmonic bonds, and like springs, are characterized by a
preferred length. The resistance to change from the optimum value is then defined by a
‘‘force constant,’’ and each bond type is thus described by at least two parameters and
the energies calculated by Hooke’s law (Eq. (1)). Here the reference bond length is l0
(Fig. 1).

Es ¼ ks ðl
l0 Þ2 ð1Þ

Hooke’s law can represent the energy increase on small distortions from the reference
value and is applied in the CHARMm force field [4] and is default in the Dreiding [5]
and UFF force fields [6]. However, for larger distortions, the energy of a true bond is
normally represented by a Morse function (Eq. (2)) that can describe the process of
dissociation energy correctly. In CVFF [7], a Morse potential is default, but a Hooke
potential may be applied. The Morse potential requires one more parameter and,
therefore, a wider range of reference data is needed for the parameterization. The
potential is given in Eq. (2), where D is the dissociation energy and a is a parameter
which, together with D, determines the curvature at the minimum.
Es ¼ Dð1
e
aðl
l0 Þ Þ2 ð2Þ
This representation is normally not needed for organic structures of a reasonable input
quality with small distortions and the difference between the two functions is then
negligible. A harmonic potential or a higher-order derivative of such is normally used
in the initial optimization phase. Additional accuracy gained from a well-determined
Morse function, at the cost of increase in complexity, may be important when studying
more complex systems.
Modified Hooke’s law corrected with cubic (as in the MM2-based force fields [8])
and further extensions to quartic terms (as in MM3 [9], CFF [10], and MMFF [11]
force fields; see Eq. (3) [9]) or other expansions [12] have been developed to mimic the
Morse potential and are used to speed up convergence in very distorted starting
geometries, while keeping a proper description of the potential energy.
Es ¼ ks ðl
l0 Þ2 ½1 þ cs ðl
l0 Þ þ qs ðl
lÞ2  ð3Þ
The simplest approach to obtaining optimized bond angles close to the reference value
h0 (Fig. 1) is to introduce a quadratic energy penalty, the harmonic approximation,
similar to the representation of bond energies (Eq. (4)), although some methods use
nonbonded interactions to model angle forces [3].
Eb ¼ kb ðh
h0 Þ2 ð4Þ

This simple representation is used in, e.g., the CVFF and CHARMm force fields. As
for bonds, two parameters are needed, a reference angle and a force constant, and only
a fraction of all the possible combinations of atom types are represented in real
chemical structures. In certain cases, generalized parameters are used because of lack
Copyright © 2004 Taylor & Francis Group LLC
 4 Liljefors et al.

of accurate reference data, e.g., using a reference value close to 109.5j for all unknown
angles around an sp3 carbon. To avoid losing the convergence properties for very
large distortions, expansions to higher order terms, similar to those in bond energies
discussed above, are applied in most force fields. Expansions to the power of four
(MMFF) and even six (MM2 and MM3) are used.
Special care has to be taken in the representations of angles of 180j, which are
wrongly represented as a cusp. To correct this problem with the slope going to zero,
trigonometric functions as exemplified in Eq. (5) can be applied [13–15]. Close to a
maximum this correction may lead to convergence problems, but this price is worth
paying in most cases.

Eb ¼ k½1 þ cosðnh þ wÞ ð5Þ

2.2. Nonbonded Interactions

Interactions between atoms that are not transmitted through bonds are referred to as
nonbonded interactions. Most interactions are between centers of atoms, while some
force fields use through-space interactions between points that are not centered on
nuclei, such as lone pairs and bond-center dipoles. Interactions between atoms sepa-
rated by only one or two bonds are normally not calculated, whereas atoms in the 1,
4-position with three intervening bonds interact both via torsional and nonbonded
potentials. Thus these interactions become partially dependent. Introduction of scal-
able parameters for nonbonded 1,4-interactions can reduce this interdependence.

2.3. Electrostatic Interactions

Calculation of electrostatic interaction energies can be done simply by using Cou-
lomb’s law, Eq. (6), providing charges q centered on each nucleus.
qi qj
Eel ¼ ð6Þ
er
Most force fields except those derived from the native MM2 and MM3 implemen-
tations apply the Coulomb potentials. Charge assignment can be done using a variety
of schemes, including fragment matching [16] and contributions through bonds [10,
17]. Furthermore, there is currently an increasing interest in polarizable force fields
incorporating electrostatics dependent on the surroundings [18]. A major problem
lies in the fact that atomic charges are statistical properties rather than observable
items, and it is not always possible to find one set of charges that will reproduce all
properties of interest. For most major force fields, one charge determination scheme
has been adopted and used in the further development of new parameter sets securing
internal consistency. Quantum mechanical calculations are generally a good source
of data for electrostatic parameters and derived charges. Inclusion of the dielectric
constant e in Eq. (6) opens the possibility of developing simple solvation models
by raising the value from 1 in the gas phase. More elaborate models are described in
Sec. 6.
Eq. (7) describes a charge model primarily based on bond-center dipoles as
applied by Allinger in MM2 and MM3 [3]. Such parameterization requires dipoles to
be determined for each bond type independent of the surroundings. v and ai, aj are the
Copyright © 2004 Taylor & Francis Group LLC
 angle between the dipoles and the angles between each dipole and the connecting
vector, respectively.
li lj
Eel ¼ 3 ðcos v
3 cos ai cos aj Þ ð7Þ
er

2.4. Van der Waals Interactions

Short-range repulsions and London dispersion attractions are balanced by a shallow
energy minimum at the van der Waals distance (Eq. (8)), describing the Lennard–
Jones’ potential, used by most force fields. Here the parameters A and B are calculated
based on atomic radii and the minimum found at the sum of the two radii.
A B
EvdW ¼
ð8Þ
r12 r6
Most force fields use the Lennard–Jones functional form or close derivatives (9-6 or
14-7 functional forms as opposed to the standard 12-6 form). To compensate for the
too hard repulsive component, MM2 and MM3 use the Buckingham potential shown
in Eq. (9).
B
EvdW ¼ Ae
ar
ð9Þ
r6

2.5. Hydrogen Bonding

The simplest way to handle hydrogen bonding is to rely on the other nonbonded
potentials to reproduce hydrogen bonds. Some methods include specific pair param-
eters [19] while others use special potentials for the nonbonded interactions between
hydrogen bond donors and acceptors [20,21].

2.6. Torsional Angles

Four consecutive atoms define the torsional bond (see Fig. 1). A large number of
different torsional types therefore exist, and general parameters for the central bond
are often used. Whereas certain preferred values for bond lengths and angles exist,
torsions are even softer than bond angles and all possible values can be found in real
structures. Thus the energy function must be valid over the entire range and,
furthermore, be periodic. For symmetry reasons, the function should have stationary
points at 0j and 180j. A simple cosine function as exemplified in Eq. (10) has been used
in the CVFF, CHARMm, and Dreiding force fields.
Et ¼ v cos nx ð10Þ
where the periodicity n is the number of minima for the potential, usually 3 for an sp3–
sp3 bond and 2 for a conjugated bond, and v is proportional to the rotational barrier.
The Fourier expansion described in Eq. (11) allows the flexibility to model more
complex torsional profiles and is used in most force fields today, including the MM2
and MM3 suite of programs. The form depicted in Eq. (11) also allows setting the
minimum contribution to zero.
Et ¼ v1 ð1 þ cos xÞ þ v2 ð1
cos 2xÞ þ v3 ð1 þ cos 3xÞ ð11Þ
Copyright © 2004 Taylor & Francis Group LLC
 6 Liljefors et al.

2.7. Out-of-Plane Bending

Special parameterization is needed to prevent atoms bound to sp2 carbons with three
substituents to deviate from planarity. Many implementations apply an energy term
Eoop that increases the energy when one of the atoms deviates from the plane defined
by the three others. Several functions have been implemented, e.g., improper torsions
or Hooke’s law functions [22,23].

2.8. Modifications
Several force fields apply various modifiers and additional terms to address specific
problems with the reduced set of standard terms. Allinger’s electronegativity effect
corrects the problem with substituents reducing the preferred bond lengths [24].
Adaptation of bond orders in conjugated systems is done by a simplified QM
interpolation scheme [25–27], and cross terms can be used to, e.g., correct for the
elongation of bonds when angles are compressed as shown in Eq. (12) [23].
Esb ¼ ksb ðh
h0 Þðl
l0 Þ ð12Þ

3. COMPARISON OF CALCULATED CONFORMATIONAL

ENERGIES
The comparison of force fields presented in this section focuses on the ability of dif-
ferent force fields to reproduce conformational energies. The relative performance
of the ability to reproduce geometries is not included as this is done reasonably well
by most force fields. The force fields included in the comparison are AMBER* [20,
28], CFF91 [10,29], CFF99 [10,29], CHARMm2.3 [4,29,30], CVFF [7,29], Dreiding
2.21 [5,29], MM2* [28], MM3*[28], MMFF [11,28], OPLS_AA [28,31], Sybyl5.21 [32,
33], and UFF1.1 [6,29]. These force fields have been selected as they are widely dis-
tributed as summarized in Table 1 and commonly used by computational and medic-

Table 1 A Summary of Different Force Fields Native to and Available in Different Software Packagesa

Cerius 2 InsightII MacroModel Quanta Sybyl5.21

(Accelrys Inc.) (Accelrys Inc.) (Schrödinger Inc.) (Accelrys Inc.) (Tripos Inc.)

AMBER*/AMBER  x 
CFF91  x
CFF99 x
CHARMm2.3  x
CVFF  x
Dreiding2.21 
MM2* x 
MM3* x
MMFF  x 
OPLS_AA x
Sybyl5.21 x
UFF1.1 
a
x = Native force field,  = available force field.

Copyright © 2004 Taylor & Francis Group LLC

 inal chemists. MM2(91) [8] and MM3(92) [9] are also included in the comparison.
The comparison is an update of previously reported evaluations [34–36]. The data set
used in the evaluation is given in Appendix A and is the same as previously employed.
For further information on the dataset and the selection of experimental values, see
Refs. [34–36].
Fig. 2 summarizes the overall results obtained by the different force fields and
for different structural classes of compounds in terms of mean absolute errors. The
performance of the force fields for particular classes of compounds is discussed in the
following sections. Fig. 2 also includes the overall results for three QM methods (PM3,
HF/6-31G* and B3LYP/6-31G*). These results will be discussed in Sec. 4.

3.1. Acyclic Hydrocarbons

As can be seen in Fig. 2, the calculated errors for the hydrocarbons in the data set are
rather small for all tested force fields. The simplest hydrocarbon that can adopt two
conformers is butane. As butane represents a fragment that can occur several times in
a molecule and thus adds up errors, it is of importance that the force field can
reproduce the experimental gauche-anti energy difference. Different experimental
values for this energy difference have been reported [37–40]. The smallest reported
experimental energy difference is 0.67 and the largest 1.09 kcal/mol. The experimental
value 0.97 kcal/mol [37] has been used in the calculations of mean absolute errors in
Fig. 2. Fig. 3 shows that all force fields correctly calculate the anti-conformer to be the
most stable conformer and that most of the force fields can reproduce the exper-
imental value within the variation of the experimental data. The force fields showing
the largest errors are UFF 1.1, AMBER*, Sybyl5.21, and CVFF.

Figure 2 Comparison of mean absolute errors (in kcal/mol) for different structural classes of
organic compounds obtained in calculations of conformational energy differences by using
different commonly used force fields.
Copyright © 2004 Taylor & Francis Group LLC
 8 Liljefors et al.

Figure 3 Calculated gauche-anti energy differences for butane in kcal/mol. The dashed hori-
zontal lines show the range of reported experimental values.

3.2. Oxygen-Containing Compounds

Fig. 2 shows that the class of oxygen-containing compounds may give rise to larger
errors than the hydrocarbons (Dreiding2.21, Sybyl5.21, and UFF1.1). For 2-methoxy-
tetrahydropyrane (Fig. 4), the anomeric effect makes the conformer with the me-
thoxy group in an axial position the most stable one by 1.0 kcal/mol [41]. Fig. 4
shows how this conformational equilibrium is handled by the different force fields.
It can be seen that four of the force fields (UFF 1.1, Dreiding2.21, CVFF, and CFF91)
are not able to predict the correct global energy minimum. It can also be seen that the
equatorial–axial energy difference is significantly overestimated by OPLS_AA and
CHARMm 2.3.

3.3. Nitrogen-Containing Compounds

All of the evaluated force fields except UFF1.1 have rather small calculated errors
for this class of compounds (Fig. 2). In order to be able to calculate the conformational
preference for peptides and other compounds containing an amide bond, the pre-
diction of the energy difference between the E and Z conformer is important. The
ability of the force fields to calculate the energy difference between the E and Z form
in N-methylacetamide is shown in Fig. 5. The experimental value is 2.3 kcal/mol [42]
and all force fields except UFF1.1 correctly predict the Z conformer to be the most
stable one. Among the force fields predicting the Z conformer to be preferred, the
largest deviations from the experimental value are shown by CVFF, Dreiding2.21,
and Sybyl5.21.
Another common fragment in medicinal chemistry is N-methylpiperidine [43].
Fig. 6 shows the calculated energy difference between the axial and equatorial con-
formers for the different force fields. All force fields correctly predict the equatorial
Copyright © 2004 Taylor & Francis Group LLC
 Figure 4 Calculated equatorial–axial conformational energy differences in kcal/mol for 2-
methoxy-tetrahydropyran. The dashed line indicates the experimental value.

conformer to be the most stable one. However, the energy difference is significantly
overestimated by UFF1.1 and underestimated by more than 1 kcal/mol by AMBER*,
CVFF, Dreiding2.21, OPLS_AA, and Sybyl5.21.

3.4. Cyclohexanes
For substituted cyclohexanes, two conformational properties are of fundamental
importance. A force field should be able to predict both the correct conformation of
the ring system and the position (axial or equatorial) of a substituent. Fig. 7 shows the
ability of the different force fields to predict the energy difference between the twist-
boat and chair conformation of cyclohexane [44]. As can be seen in the figure most
of the force fields reproduce this well. However, the energy difference is overestimated
by several of the force fields, in particular by CVFF and UFF1.1.
For testing the ability of the force fields to reproduce the energy difference
between an axial and equatorial substituent, methylcyclohexane and aminocyclohex-
ane have been chosen as examples. The experimental value for the energy difference
between the two chair conformers in methylcyclohexane is 1.75 kcal/mol [45]. All force
fields correctly calculate the equatorial conformer to be the most stable one as dis-
played in Fig. 8. Again, the energy difference is strongly overestimated by CVFF and
UFF1.1.
For aminocyclohexane, the experimental value for the energy difference between
the axial and equatorial conformer is 1.49 kcal/mol with the equatorial conformer
as the most stable one [46]. In Fig. 9 it is shown that AMBER* predicts the axial
Copyright © 2004 Taylor & Francis Group LLC
 10 Liljefors et al.

Figure 5 Calculated energy differences in kcal/mol between the E and Z conformer of N-

methylacetamide. The dashed line indicates the experimental value.

Figure 6 Calculated conformational energy differences (axial–equatorial) in kcal/mol for N-

methylpiperidine. The dashed line shows the experimental value.
Copyright © 2004 Taylor & Francis Group LLC
 Figure 7 Calculated energy differences in kcal/mol between the twist-boat and chair
conformers of cyclohexane. The dashed line indicates the experimental value.

conformer to be the most stable one and that Sybyl5.21 predicts the two conformers
to be essentially equally stable. It can also be seen that the energy difference is sig-
nificantly underestimated by CFF91, CF99, Dreiding2.21, and MMFF and overesti-
mated by CVFF, OPLS_AA, and UFF1.1.
In conclusion, the overall results displayed in Fig. 2 show that for the data set
employed in this comparison of force fields the best results are obtained by MM2*,
MM2(91), MM3*, MM3(92), MMFF, and CHARMm. The least successful results
are clearly obtained by CVFF, Dreiding 2.21, and UFF1.1.

Figure 8 Calculated conformational energy differences between axial and equatorial

methyl-cyclohexane in kcal/mol. The dashed line shows the experimental value.
Copyright © 2004 Taylor & Francis Group LLC
 12 Liljefors et al.

Figure 9 Calculated energy differences in kcal/mol between axial and equatorial amino-
cyclohexane. The dashed line indicates the experimental value.

4. COMPARISON OF QUANTUM MECHANICS

AND MOLECULAR MECHANICS
Quantum mechanical methods have been undergoing an explosive development in
the last decade, in performance but even more in accessibility [1]. At present, several
QM methods can routinely be applied to geometry optimization and evaluation of
conformational energies for small organic molecules. This has traditionally been the
domain of force-field methods. Furthermore, QM results are increasingly being used
in the development of new force fields [10,11,47]. It is therefore relevant to compare
the performance of some commonly employed QM methods with that of the force
fields evaluated above. Halgren has published a similar comparison employing cor-
related methods (MP2 and higher) used in the development of the MMFF force field
[11]. We will instead compare with faster methods more frequently used in evaluating
conformational energies. To differentiate the methods, we will use a Student’s t test
to evaluate whether one method is more accurate than another for the data set em-
ployed. If nothing else is stated, we test at a confidence level of 90%. Data for most
force fields were taken from the literature [30,35]. Updated and newly determined
results can be found in Appendix A. The mean absolute errors (MAEs) for each force
field and for three QM methods are depicted in Fig. 2.
The Hartree–Fock (HF) level was included in the test because it has been the de
facto standard for many years. More and more, it is being replaced by DFT-based or
correlated methods, but it is still in common use. As an example of a currently popular
DFT method we have chosen B3LYP [48], a hybrid functional employing three em-
Copyright © 2004 Taylor & Francis Group LLC
 pirical parameters to weigh the contributions from HF exchange and different DFT
functional components. This method has been shown to be a good alternative to high-
level ab initio methods for many types of energy comparisons [49]. Both methods have
been employed with the 6-31G* basis set. A frequently employed method is to
calculate the energies at a correlated level using geometries from a simpler calculation.
This has been done here using the MP2/6-31+G** method with either HF or B3LYP
geometries (see Appendix A) in the Jaguar [50] and Gaussian98 [51] programs. Finally,
we have tested two popular semi-empirical methods, AM1 [52] and PM3 [53]. For
conformational energies of molecules with around 1000 atoms, semiempirical meth-
ods are still the only feasible QM alternatives. The difference between these two
methods was not statistically significant, but PM3 gave a slightly lower total error in
the test and was therefore used in all comparisons.
Comparing the QM methods to each other (see Fig. 2 and Appendix A), we can
see that the MAE over the entire set of conformational energies is 0.49 kcal/mol for
B3LYP, 0.66 kcal/mol for HF, and 1.37 kcal/mol for PM3. We can say with 98%
confidence that B3LYP is more accurate than HF for this type of comparison, and
with more than 99.9% confidence that both methods are better than PM3. Thus the
three methods form a convenient scale for grading the force-field methods. The two
MP2 methods are not shown in Fig. 2, as both overall appearance and MAE are
similar to B3LYP (MAE 0.48 and 0.50 kcal/mol, respectively; see Appendix A). An
interesting corollary of the MP2 results is that the geometries from HF and B3LYP are
of similar quality for this type of comparison. They are not identical, but differences
are obviously systematic and thus cancel in a comparison of conformational energies.
Looking at the force fields, we can see that most of them fall in about the same
accuracy range as the QM methods (Fig. 2). The two best force fields, MM2* and
MMFF, are significantly better than HF (>95%) and are not significantly different
from B3LYP. It should be noted that force fields are limited compared to QM methods
in that they are only applicable to molecules with identical connectivity (e.g., con-
formations and possibly stereoisomers), and then only for systems where parameters
have been well determined. However, within this limitation, it is noteworthy that the
best force fields are as accurate as any affordable QM method and certainly many
orders of magnitude more cost effective. This also makes clear that parameterization
of force fields requires methods that are significantly better than HF [11a], because
the best possible result in parameterizing a force field is to reproduce the reference
data exactly.
Following this star group, we find a set of force fields which are not significantly
better than HF, but nor are these significantly worse than B3LYP, with mean errors
up to 0.67 kcal/mol. These include most of the MM2 and MM3 implementations, as
well as CHARMm. It is also quite probable that with a complete set of parameters,
CFF91 and CFF99 would fall within this group. However, detailed halogen param-
eters are unavailable for the CFF methods, which causes the program to automatic-
ally supply rule-based parameters of a lower quality. For this reason, we cannot grade
CFF with certainty. Closely following this group is a single force field, the newly im-
plemented OPLS_AA force field, with a performance probably worse than B3LYP
(MAE = 0.75 kcal/mol).
It is significant that the group of force fields with an accuracy at least equal to
HF all contain some well-parameterized cross terms. Obviously, a few such terms are
necessary for an accurate calculation of conformational energies. The best parame-
Copyright © 2004 Taylor & Francis Group LLC
 14 Liljefors et al.

terized diagonal (i.e., lacking cross-terms) force field in the study, AMBER*, yielded
an MAE of 0.87 kcal/mol. This is significantly worse than HF (and indeed AMBER
is extensively parameterized from HF), but it is still better than the Tripos force field
in Sybyl (MAE = 1.07 kcal/mol). However, both are significantly more accurate than
the semi-empirical method PM3.
In the next group, we find early diagonal force fields included in previous studies
[35] but not in Fig. 2, such as an earlier version of the Tripos force field and ChemX,
but also a rule-based force field, Dreiding (included in Fig. 2). All of these have about
the same accuracy as the PM3 method. The early diagonal force fields are still being
used to some extent but are slowly being replaced by more modern force fields.
However, it is interesting to note that for conformational energies of large systems
beyond the scope of the HF method and if the presence of unknown groups make
application of specifically parameterized force fields impossible, a rule-based force
field is preferable to a semiempirical calculation. It has about the same accuracy and is
still many orders of magnitude faster than PM3.
A few force fields have an accuracy worse than that of semiempirical methods.
CVFF was developed from an initially diagonal force field by adding a large number
of cross terms, with insufficient reparameterization. It is obvious that this resulted
in a force field with low predictivity, and its use cannot be recommended for any
application. UFF was intended to cover the entire periodic table and is still the only
published force field that can accomplish this task. However, the accuracy for or-
ganic molecules was sacrificed in the process: the MAE for UFF is ca. 3 kcal/mol.
The force fields can also be compared to a ‘‘blank’’ result, the mean absolute
of all conformational energies to be predicted. This is the performance that would be
expected by any random-number generator symmetrically centered around 0 kcal/
mol. Most force fields yield a performance substantially better than this random
guess, but of the methods considered here, CVFF is not significantly different from
the blank, and UFF is actually worse.

5. INTERMOLECULAR INTERACTIONS
Calculations of intermolecular interactions are extremely important in many aspects
of modern medicinal chemistry. Docking of ligands into cavities in targets is used in
structure-based design and precise estimation of ligand–target energetics is required to
predict binding affinities. A prerequisite to do reasonable qualitative docking is to have
a well-defined target and a good parameterized method for calculating intermolecular
interactions. These are quite difficult to calculate and quantification of binding ener-
gies requires even better methods. Clearly, the best understood experimental cases are
crystal structures, and parameterization is often based on such studies. In the absence
of experimental data, high-level ab initio calculations can be used for computations
of intermolecular energies and geometries, and the results may be employed in the
parameterization process.
Electrostatic and van der Waals intermolecular interactions are involved in the
binding process. Apart from a valid description of the conformational energies, ac-
curate description of these interactions is crucial for the determination of intermolec-
ular energies. The energy functions in the MM methods are normally parameterized
against standard models, which involve interactions between atoms as in hydrogen

Copyright © 2004 Taylor & Francis Group LLC

 bonding. Other important interactions include those between aromatic moieties in
receptor–ligand interactions. It has been known for a long time that charge–transfer
interactions between electron-rich and electron-deficient rings occur. Weaker inter-
actions from the edge to the face of rings are also important [54].
An extensive comparative study on intermolecular interactions has been made
by Halgren [11b,11g]. Interaction energies in small model systems calculated by
MMFF94, MM2, MM2X, MM3, OPLS, and CHARMm [11b] were compared with
high-level ab initio energies. Important differences between these methods stem from
differences in their charge models. The neglect of polarizability is a limitation of all
the models. In general terms, MMFF94 and MM3 performed well in nonbonded
aliphatic systems. Considering hydrogen bonding, MMFF94 and OPLS in most cases
correctly predict interaction energies within 10% and also manage to correctly classify
the strengths of hydrogen bond acceptors and donors. Predictions of geometries
of the complexes are good with the largest discrepancies in weakly bound sulfur-
containing complexes.
In an extended comparison of intermolecular interaction energies and dis-
tances based on scaled HF/6-31G* data for 66 hydrogen-bonded complexes and in-
cluding the MMFF94, MMFF94s, CFF95, CVFF, CHARMm, CHARMM22,
OPLS*, AMBER*, MM2*, and MM3* force fields, the MMFF94/MMFF94s and
CHARM22 force fields clearly performed best [11g]. The next best performance was
displayed by the AMBER* force field followed by OPLS* and CFF95.

6. FORCE-FIELD CALCULATIONS INCLUDING SOLVATION

As described above, force fields are generally developed and validated for gas phase
properties on the basis of gas-phase experimental data or from data obtained in low
dielectric solvents. More recently, data from high-level ab initio calculations have
been employed. Thus straightforward force-field calculations refer to molecules in
vacuo. However, solvation plays an important role in many aspects of chemistry in
general and of medicinal chemistry in particular. For instance, most compounds of
relevance for medicinal chemistry are flexible and very often have polar functional
groups. As the most important solvent in medicinal chemistry is water, conforma-
tional properties in this highly polar solvent may be drastically different from the
properties in vacuo and only calculations including the solvent may yield meaningful
results. Calculations on various aspects of ligand–enzyme/receptor interactions and
partitioning between phases require the consideration of solvation effects. Thus the
accurate estimation of solvent effects is a key problem in computational medicinal
chemistry.

6.1. Explicit vs. Implicit (Dielectric Continuum) Solvation

Models
The most straightforward way to account for solvation effects is to explicitly include
a large number of solvent molecules in the calculations. However, this requires the
explicit consideration of hundreds or thousands of solvent molecules around the
solute. In addition, the need for the generation of a large number of water config-

Copyright © 2004 Taylor & Francis Group LLC

 16 Liljefors et al.

urations requires Monte Carlo or molecular dynamics methodologies to be employed,

resulting in a very high computational cost. This problem has led to the development
of implicit solvation models in which the solvent is treated as a polarizable continuous
medium surrounding the solute beginning at or near its van der Waals surface. The
solvent is then characterized by its bulk dielectric constant. Such methods are orders
of magnitude faster to use in calculations of solvent effects compared to explicit solva-
tion models and have therefore received much attention in computational medicinal
chemistry. A disadvantage of implicit solvation models is that no structural informa-
tion on specific solvent–solute interactions can be obtained.
The most rigorous dielectric continuum methods employ numerical solutions
to the Poisson–Boltzmann equation [55]. As these methods are computationally quite
expensive, in particular in connection with calculations of derivatives, much work
has been concentrated on the development of computationally less expensive approx-
imate continuum models of sufficient accuracy. One of the most widely used of these
is the Generalized Born Solvent Accessible Surface Area (GB/SA) model developed
by Still and coworkers [56,57]. The model is implemented in the MacroModel pro-
gram [17,28] and parameterized for water and chloroform. It may be used in conjunc-
tion with the force fields available in MacroModel, e.g., AMBER*, MM2*, MM3*,
MMFF, OPLS*. It should be noted that the original parameterization of the GB/SA
model is based on the OPLS force field.
Dielectric continuum models have also been developed to be used in conjunction
with ab initio as well as semiempirical quantum chemical methods. For a compre-
hensive discussion on dielectric continuum models in general and on its use in
connection with quantum chemistry calculations in particular, the reviews by Cramer
and Truhlar are highly recommended [58].
As the present chapter is restricted to force-field calculations, only the GB/SA
dielectric continuum model and similar models will be discussed. The aim is not to give
an exhaustive review of the rapidly increasing literature in this area but to describe the
basic properties of the GB/SA model and to discuss some aspects of the model and its
use that are of particular interest in computational medicinal chemistry.

6.2. The GB/SA Model

In the GB/SA model, the solvation free energy ( Gsolv) is calculated as a sum of three
terms

Gsolv ¼ Gcav þ GvdW þ Gpol ð13Þ

where Gcav is the cavitation energy, i.e., the free energy required to form a cavity in the
solvent in which the solute is embedded. GvdW is the solute–solvent van der Waals
energy (first hydration shell effects) and Gpol the solute–solvent electrostatic polar-
ization energy. The sum of Gcav+GvdW is taken to be proportional to the solvent
accessible surface (SA) of the solute and is calculated as the sum of atomic surface area
contributions SAk multiplied by an empirical atomic solvation parameter rk for atoms
of type k as shown in Eq. (14).
X
Gcav þ GvdW ¼ rk SAk ð14Þ

Copyright © 2004 Taylor & Francis Group LLC

 The Gpol term is calculated by the generalized Born equation (Eq. (15))

 n
1 X
 n 2
1 X n
qi qj 1 X qi
DGpol ¼
332 1

166 1
ð15Þ
e i¼1 j¼iþ1 rij e i
ai

modified in Eq. (16) to allow for irregularly shaped solutes.

 n X
1 X n
qi qj
DGpol ¼
166 1
ð16Þ
e i¼1 j¼1 ðrij þ a2ij e
Dij Þ0:5
2

where aij=(aiaj)0.5 and Dij=rij2/(2aij)2.

A computationally efficient analytical method has been developed for the crucial
calculation of Born radii, which is required for each atom of the solute that carries a
(partial) charge, and the Gpol term has been parameterized to fit atomic polarization
energies obtained by Poisson–Boltzmann equation [57]. The GB/SA model is thus
fully analytical and affords first and second derivatives allowing for solvation effects to
be included in energy minimizations, molecular dynamics, etc. The Gpol term is most
important for polar molecules and describes the polarization of the solvent by the
solute. As force fields in general are not polarizable, it does not account for the
polarization of the solute by the solvent. This is clearly an important limitation of this
type of calculations.
Qui et al. have compared experimental and calculated hydration free energies for
a set of 35 small organic molecules with diverse functional groups by using the OPLS
force field and the GB/SA hydration model [57]. These calculations resulted in a mean
absolute error of 0.9 kcal/mol. It is of interest to note that the results obtained with the
GB/SA model were very similar to those obtained by the corresponding calculations
using the full Poisson–Boltzmann equation.

6.3. Comparisons of Calculations Employing Explicit

and Implicit Solvation Models
In the first paper reporting the GB/SA model, Still and coworkers compared the
calculated Gpol values obtained by the GB/SA algorithm with the corresponding
values obtained by free-energy perturbation (FEP) calculations using explicit solva-
tion with TIP4P water molecules [56]. For the neutral compounds in the dataset, a
linear correlation between the two sets of calculated values was obtained with a slope
of 1.1 and a correlation coefficient of 0.98. Thus the results obtained by two different
types of solvation models are very similar. The same conclusion was drawn by Reddy
et al. on comparing the results of Monte Carlo-free-energy perturbation calcula-
tions with explicit TIP4P waters with the corresponding results from GB/SA calcula-
tions [59]. Thus at least for simple neutral organic compounds there is no need for
computationally expensive explicit solvent simulations for estimating free energies
of hydration.
As an example of the relative performance of explicit and implicit solvation
models in calculations of conformational equilibria, Scarsi et al. [60] compared the
calculated conformational properties obtained by the CHARMM force field of liquid
1,2-dichloroethane and of terminally blocked alanine dipeptide in aqueous solution.
They employed (i) a systematic conformational search with solvation energies cal-

Copyright © 2004 Taylor & Francis Group LLC

 18 Liljefors et al.

culated by a dielectric continuum generalized Born model similar to the Gpol part in
GB/SA, and (ii) molecular dynamics simulations including 216 1,2-dichloroethane
molecules and 207 water molecules, respectively. Good agreement between the results
obtained by the two computational methods were shown for both cases. The increase
in the gauche/trans ratio for 1,2-dichloroethane on going from gas phase to the liquid
phase as experimentally observed was reproduced by both methods.

6.4. The Dependence of Calculated Hydration Energies

on Different Charge Sets
As mentioned above, the accurate calculation of the electrostatic contribution ( Gpol) is
crucial for the calculation of hydration free energies for polar molecules. This implies
that the quality of the atom-centered partial charges used by the force field to describe
electrostatic interactions is of decisive importance for the results. The atomic partial
charges in the various force fields are assigned in different ways. For instance, the basic
OPLS* charge set is based on liquid-phase simulations in explicit solvents, but more
recent versions also employ fitting of partial charges to the electrostatic potential
surface calculated by ab initio calculations [31]. The AMBER* force field also uses
charges derived from fitting to molecular electrostatic potentials. In contrast, the
partial charges in MM2* and MM3* are derived from the empirically determined
bond dipoles in the ‘‘authentic’’ parent programs MM2 [3,8] and MM3 [9]. Charges
for MMFF are basically calculated to mimic electrostatic potential derived charges
calculated by using the HF/6-31G* basis set and formulated as ‘‘bond charge incre-
ments’’ to be added to full or fractional ‘‘formal atomic charges’’ [11b]. It is important
to note that the assigned partial charges in all force fields are an integral part of the
force field and should not be modified by the user.
Reddy et al. have systematically studied the sensitivity of hydration free ener-
gies calculated using the GB/SA model on different charge sets and force fields [59].
Using a small database of 11 monofunctional compounds with standard geometries
and using single-point energy calculations, they compared the calculated free ener-
gies of hydration for force fields available in Macromodel (MM2*, MM3*, OPLS*,
AMBER* and MMFF). The charge sets of OPLS* and AMBER* clearly performed
best with mean absolute errors (MAE) of 1.02 and 1.38 kcal/mol, respectively, whereas
those of MM3* (MAE=1.82 kcal/mol) and in particular MM2* (MAE = 2.65 kcal/
mol) display significantly inferior performance. The results obtained by MMFF were
of similar quality as MM3* (MAE = 1.97 kcal/mol). The good performance of the
OPLS* charge set is not surprising as the original GB/SA parameterization was
based on the OPLS force field. As noted by Reddy et al., it is likely that reparam-
eterization of GB/SA for a particular force field may improve the results for the force
field. This has been demonstrated by Cheng et al. [61], who partly reparameterized
the GB/SA model for the MMFF force field with a resulting significant improvement
in performance. An average unsigned error of 0.74 kcal/mol for 129 neutral com-
pounds was obtained to be compared with an error of 1.43 kcal/mol from using the
original GB/SA model with MMFF. A generalized Born model with parameters spe-
cifically tailored to the AMBER force field has been reported by Jayaram et al. [62].
The force field dependence on calculated conformational equilibria in aqueous
solution has been demonstrated in a study of the strongly polar ionotropic glutamate

Copyright © 2004 Taylor & Francis Group LLC

 receptor agonist kainate [63]. Conformational analyses of kainate in aqueous solution
were performed using the MM3*, AMBER*, and MMFF94 force fields in conjunction
with the GB/SA hydration model. The conformational properties of kainate in
aqueous solution have been studied by Todeschi et al. using 13C and 1H NMR spec-
troscopy [64]. The experimental data indicate that the predominating conforma-
tion of kainate is of type A (Fig. 10), with no significant contribution of the internally
hydrogen bonded type B conformation.
AMBER*+GB/SA and MMFF94+GB/SA predict that the conformational
ensemble consist of 72% and 83%, respectively, of type A conformers, whereas 96% of
the MM3* conformational ensemble consists of type B conformers with one strongly
dominating conformer. This study indicates that MM3*+GB/SA strongly overesti-
mates the stability of the hydrogen bonded ion-pair in aqueous solution as shown by
conformer B, in comparison with the separated ions as in conformer A.

6.5. Calculations of Conformational Energy Penalties

for Ligand–Protein Binding
Calculated conformation energy penalties for ligand binding are useful in, e.g.,
pharmacophore modeling and structure-based ligand design. In pharmacophore
modeling, such energies may be employed to find suitable candidates for the bioactive
conformations of a set of molecules. In structure-based ligand design it is necessary to
ensure that the designed ligand does not require a prohibitively high conformational
energy for binding to the receptor. This is important as the equation DG=RTlnKi
implies that each 1.4 kcal/mol (T=300 K) of increased conformational energy of the
bound conformation leads to a decrease in the affinity by a factor of 10.
High conformational energy penalties have often been reported in the literature.
For instance, Nicklaus et al. studied 27 flexible ligands extracted from experimentally
determined ligand–protein complexes and obtained calculated energy differences
between the protein-bound and unbound conformations between 0 and 39.7 kcal/
mol with an average of 15.9 kcal/mol [65]. The most important reason for these high
energies is that the calculations were performed for gas phase. Such calculations are
not meaningful in connection with structure–activity studies and ligand design, as it is

Figure 10 Conformational equilibrium for kainate involving separated ions (A) and inter-
molecular ion-pair hydrogen bonding (B).

Copyright © 2004 Taylor & Francis Group LLC

 20 Liljefors et al.

clear that the aqueous conformational ensemble for the unbound ligand must be used
as the reference state in this type of calculations [66].
This has been demonstrated in a study of 33 ligand–protein complexes includ-
ing 28 different ligands using the MM3* and AMBER* force fields with the GB/SA
hydration model [66]. By using the aqueous conformational ensemble for the un-
bound ligand as the reference state, the great majority of conformational energy pen-
alties for binding were calculated to be smaller than 3 kcal/mol. As an example of the
strong influence of solvent effects in this type of calculations, the preferred confor-
mation of biotin in vacuo displays a strong hydrogen bond between the carboxylate
group and the NH group (Fig. 11a). However, in aqueous solution biotin strongly
prefers an extended conformation (Fig. 11b) according to MM3* as well as AMBER*.
The conformation of biotin bound to the enzyme streptavidin is shown in Fig. 11c.
Using the in vacuo conformation as the reference state for calculating the confor-
mational energy penalty gives a calculated energy penalty of 12.8 kcal/mol (MM3*)
and 6.4 kcal/mol (AMBER*). These high energies are clearly not compatible with the
very high affinity of biotin to streptavidin (Ka = 2.5  1013, DG =
18.3 kcal/mol,
DH =
32 kcal/mol). When using the predominating conformation in aqueous

Figure 11 Calculated lowest energy conformations for biotin in (a) gas phase and (b) aqueous
phase. The conformation observed in the biotin–streptavidine ligand–protein complex (pdb-
code: 1stp) is shown in (c).
Copyright © 2004 Taylor & Francis Group LLC
 phase as the reference conformer, the corresponding energies are calculated to be
small, less than 1.6 kcal/mol.
Dielectric continuum models are excellent tools for fast and reliable calculations
of hydration energies and solvent effects on, e.g., conformational equilibria, ligand–
receptor interactions, and partitioning phenomena. For neutral solutes, the perform-
ance of such solvation models is already very good, whereas calculations on ionic
compounds still pose significant problems. Force fields that include polarization
effects may be required for accurate calculations on strongly polar molecules. A
problem in the further development and validation of solvation models is the lack of
experimental data for, e.g., conformational equilibria in aqueous solution. For
optimal accuracy of calculations using a dielectric continuum model, it would be an
advantage if the model is parameterized for the particular force field to be used.

7. CONCLUSION
The ability of 14 widely distributed and commonly used force fields to reproduce
experimental conformational energies for a data set of 44 conformational energy dif-
ferences or rotational barriers has been compared. The results show that the best
results are obtained by the MM2*, MM2(91), MM3*, MM3(92), MMFF, and
CHARMm force fields, whereas the least successful results are obtained by the CVFF,
Dreiding2.21, and UFF1.1 force fields. AMBER*, CFF91, CFF99, OPLS_AA, and
Sybyl5.21 display results of intermediate quality. A further comparison was made with
results obtained by the semiempirical PM3, ab initio HF/6-31G* and density func-
tional B3LYP/6-31G* calculations. (Among the quantum chemical methods them-
selves B3LYP is, as expected, more accurate than HF, and both methods are better
than PM3.) A significant result of this comparison is that the best force fields are as
accurate, for the data set used, as the QM methods and certainly many orders of
magnitude more cost effective. The two best force fields, MM2* and MMFF, are
significantly better than HF/6-31G* and are not significantly different from B3LYP/6-
31G*. It is concluded that parameterization of force fields from data obtained by
quantum mechanics methods requires methods that are significantly better than HF.
The group of force fields with an accuracy at least equal to HF all contain some well-
parameterized cross terms. All force fields tested, except CVFF and UFF1.1, perform
better than the semiempirical PM3 method.
For calculations on intermolecular interactions, the extensive comparisons re-
ported by Halgren clearly show that for hydrogen-bonded complexes the MMFF94/
MMFF94s and CHARM22 force fields perform best, followed by AMBER*, OPLS*,
and CFF95. For nonbonded aliphatic systems, MMFF94 and MM3 are the best
performers. The neglect of polarizability is a limitation for all current force fields.
Dielectric continuum models such as the Generalized Born Solvent Accessible
Surface Area (GB/SA) model are, in conjunction with force fields, excellent tools for
fast and reliable calculations of hydration energies and solvent effects on, e.g., con-
formational equilibria and ligand–receptor interactions. The performance for neu-
tral solutes is very good, whereas calculations on ionic compounds are currently
more problematic. A solution to these problems most probably requires force fields
that include polarization effects. For optimal accuracy of calculations using a dielec-
tric continuum model, it is a clear advantage if the model is parameterized for the
particular force field used.
Copyright © 2004 Taylor & Francis Group LLC
Appendix Updated MM and newly determined QM energies, in kcal/mol. Conformational equilibria and selection of experimental values are described
in the main text and Ref. [35].
Macromodel 7.2 Cerius2 Jaguar v. 4.1 Gaussian 98, rev. A.7

MM2* MM3* Amber* MMFF OPLS_AA CFF99 HF/6-31G* B3LYP/6-31G* HF/6-31G* B3LYP/6-31G* MP2a//HF MP2a//B3LYP Exp.

Ethane, TS-GS 2.7 2.4 2.8 3.2 2.8 2.6 3.0 2.8 3.0 2.8 3.2 3.2 2.9
Propene, TS-GS 2.1 1.7 1.6 2.0 1.9 1.7 2.1 2.1 2.1 2.1 1.9 1.9 2.0
Isoprene, TS-GS 2.9 0.8 1.4 3.1 1.0 2.6 2.9 2.5 2.9 2.5 2.7 2.7 2.7
Ethylbenzene, TS-GS 1.5 1.8 0.4 1.2 1.4 1.7 1.4 1.1 1.4 1.1 1.5 1.6 1.7
Trimethyl isopropyl 11.0 10.9 10.4 12.9 13.3 11.1 14.8 12.8 14.6 12.7 12.2 12.3 12.8
benzene, TS-GS
Styrene, TS-GS 1.7 3.3 2.4 1.0 3.0 1.1 2.9 4.4 2.9 4.4 2.2 1.8 1.8
Butane, g–a 0.9 0.8 0.5 0.8 0.8 0.9 1.0 0.8 1.0 0.8 0.7 0.7 1.0
2,3-Dimethylbutane, g–a 0.1 0.4
0.1
0.2
0.2 0.5
0.1 0.1
0.1 0.0 0.1 0.1 0.1
1,3,5-Trineopentylbenzene, 0.8 0.4 0.3 0.5 0.7 0.5
0.2
0.1
0.2
0.1 0.2 0.1 1.0
twosyn–allsyn
Methyl acetate, 5.6 7.0 6.4 8.3 9.0 8.7 9.4 7.8 9.4 7.8 8.6 8.6 8.0
cis–trans (CMO)
2-Butanone, skew-ecl 1.6 1.6 1.6 0.8 0.0 1.4 1.5 1.5 1.5
0.0 1.0 0.0 2.0
(CMO)
Ethyl methyl ether, g–a 1.7 1.5 1.4 1.5 1.5 1.5 1.7 1.4 1.7 1.4 1.4 1.4 1.5
2-Methoxy-THP, eq–axb 0.5 0.9 1.4 1.8 3.2 1.9 1.0 0.8 1.1 0.9 1.3 1.4 1.0
Ethanol (C–O), g–a 0.6 0.4 0.2 0.2 0.1 0.4 0.1
0.3 0.1
0.3 0.2 0.1 0.7
Propanol (C–C), g–a 0.3 0.4
0.2 0.3
0.1 0.3
0.1
0.1
0.1
0.1
0.3
0.3
0.3
Ethyl amine (C–N), g–a
0.1
0.1
0.1
0.4 0.0
0.2
0.1 0.4
0.1 0.4
0.2
0.2 0.7
N-Methylacetamide, E-Z 1.9 2.6 1.9 2.2 2.3 3.1 2.5 1.9 2.5 2.5 2.4 2.1 2.4
N-Methylpiperidine, ax–eq 2.5 2.3 1.3 3.3 2.1 3.3 3.6 3.4 3.6 3.4 3.9 3.9 3.2
2-Methylpiperidine, ax–eq 2.1 2.3 1.2 2.4 2.3 2.4 3.1 3.0 3.1 2.9 3.1 3.1 2.5
3-Methylpiperidine, ax–eq 1.6 1.5 0.5 1.1 2.3 1.4 1.6 1.6 1.6 1.6 1.3 1.3 1.6
4-Methylpiperidine, ax–eq 1.7 1.7 1.1 1.4 2.5 1.8 2.5 2.4 2.4 2.4 2.3 2.3 1.9

Copyright © 2004 Taylor & Francis Group LLC

Cyclohexane, twist-chair 5.4 6.5 5.8 5.9 7.0 7.1 6.8 6.5 6.8 6.5 6.6 6.6 5.5
Phenylcyclohexane, ax–eqb 3.9 4.3 2.0 2.3 4.0 3.9 4.2 3.6 4.2 3.6 3.6 3.5 2.9
Methylcyclohexane, ax–eq 1.8 1.8 1.0 1.4 1.8 1.8 2.3 2.2 2.3 2.2 2.0 2.0 1.8
Aminocyclohexane, ax–eqb 1.4 1.2
0.3 0.8 2.5 0.4 1.1 1.4 1.1 1.4 1.1 1.0 1.5
N,N-Dimethylamino- 1.0 1.2 1.2 1.4 5.5 1.0 2.1 1.8 2.1 1.8 0.4 0.4 1.3
cyclohexane, ax–eqb
trans-1,2-Dimethylcyclohexane, 2.4 2.6 1.3 1.8 2.3 2.7 3.2 3.1 3.2 3.1 2.8 2.7 2.6
ax,ax–eq.eq
cis-1,3-Dimethylcyclohexane, 5.3 5.7 4.4 5.1 5.4 5.4 6.6 6.0 6.5 5.9 5.8 5.7 5.5
ax,ax–eq.eq
FCH2CH2F, g–a
0.6
0.6 0.8
0.6
0.6 1.6 0.5
0.4 0.5
0.4
0.5
0.5
0.8
PrCl, g–a 0.2 0.3 0.2 0.0
0.3 1.0 0.4 0.1 0.4 0.2 0.1 0.1
0.2
ClCH2CH2Cl, g–a 0.4 1.4 0.7 1.2 0.8 1.2 1.9 1.7 1.9 1.7 1.5 1.4 1.1
ClCH2CH2CH2Cl, g,a–g,g 0.3 0.0
0.2 0.4
0.2
0.9 0.4 0.7 0.4 0.7 0.7 0.7 1.1
ClCH2CH2CH2Cl, a,a–g,g 0.8 0.2
0.1 1.1
0.1
1.9 0.8 1.3 0.8 1.3 1.3 1.3 1.5
F, ax–eq 0.2 0.2 0.3
0.4 0.3 1.6
0.3
0.2
0.3
0.2
0.2
0.1 0.2
Cl, ax–eq 0.4 0.6 0.5
0.3
0.2 1.7 1.0 0.8 1.0 0.8 0.9 1.0 0.5
Br, ax–eq 0.5 0.6 0.8 0.0 0.3 2.1 0.9 0.7 0.0
0.2 0.2 0.2 0.7
trans-1,2-diF, ax,ax-eq,eq 0.8 0.9
0.3
0.2 1.4 1.7
1.4
0.8
1.4
0.8
0.8
0.8 0.6
trans-1,2-diCl, ax,ax-eq,eq 0.9
0.4 0.1
2.0
2.2 2.2
0.4
0.6
0.4
0.5
0.2
0.1
0.9
trans-1,2-diBr, ax,ax-eq,eq
0.7
0.4 0.7
1.7
2.3 1.7
2.0
2.1
2.5
2.5
3.2
3.0
1.5
trans-1,4-diF, ax,ax-eq,eq
0.5
0.3
0.2
2.6
0.5 2.7
1.7
1.5
1.7
1.5
1.9
1.9
1.1
trans-1,4-diCl, ax,ax-eq,eq 0.3 0.7 0.1
2.0
0.5 3.4 0.8 0.3 0.8 0.3 0.6 0.6
0.8
trans-1,4-diBr, ax,ax-eq,eq 0.6 0.9 1.2
0.8
0.6 3.1 0.4
0.1
1.4
1.8
1.0
1.0
0.9
Butadiene, s-cis–s-trans 2.7 1.7 3.2 3.4 3.6 2.9 3.1 3.9 3.0 3.5 2.6 2.8 2.5
Acrolein, s-cis–s-trans 1.6 1.9 2.4 2.0 2.6 1.8 1.7 1.7 1.7 1.7 1.9 2.0 1.7
Root mean square error (RMS) 0.72 0.80 1.07 0.61 1.07 1.58 0.84 0.69 0.82 0.75 0.62 0.67 3.00c
Mean absolute error (MAE) 0.48 0.58 0.87 0.50 0.75 1.06 0.66 0.49 0.66 0.54 0.48 0.50 2.02c

a
MP2/6-31+G** single-point energies at the indicated G98 geometries.
b
Total energy calculated by including contributions from up to three side chain rotamers.
c
Deviation from zero, the expected error from a random-number generator centered around zero.

Copyright © 2004 Taylor & Francis Group LLC

 24 Liljefors et al.

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 2
Semiempirical Methods

THOMAS BREDOW
University of Hannover, Hannover, Germany

1. INTRODUCTION
Like ab initio methods, semiempirical approaches are based on the electronic Schrö-
dinger equation (1) obtained after separation of nuclear and electronic motion (Born–
Oppenheimer approximation) [1].
Ĥðr; RÞCðr; RÞ ¼ E el ðr; RÞCðr; RÞ ð1Þ
Here r and R denote the coordinates of electrons and nuclei, respectively. The Ham-
ilton operator H contains operators for the kinetic energy of the electrons, T̂, their
electrostatic interaction with the nuclei V̂en, and among themselves V̂ee.
Ĥðr; RÞ ¼ T̂ þ V̂en þ V̂ee ð2Þ
The total energy E of the system is obtained by adding the nuclear repulsion Vnn (a
classical sum of Coulomb interactions) to the electronic energy.
Eðr; RÞ ¼ E el ðr; RÞ þ Vnn ð3Þ
The binding energy EB of a molecule is the energy gain due to bond formation with
respect to the isolated atoms I in the gas phase.
X
EB ¼ E
EI ð4Þ
I

Two fundamental methodologies have been developed to solve the electronic Schrö-
dinger equation (1) from first principles. The Molecular Orbital (MO) theory aims at
finding an expression for the wave function W, while in Density Functional Theory
(DFT), the electron density distribution q plays this role. These methods are described
in detail in other chapters of this book. Their advantage is that they can, in principle,
Copyright © 2004 Taylor & Francis Group LLC
 30 Bredow

provide an exact numerical solution to Eq. (1) provided that the convergence with
respect to the inherent technical parameters (i.e., the completeness of the active space
in multireference-determinant MO theory approaches, the quality of the exchange-
correlation functional in DFT methods, and the basis set size for both) has been
achieved. A disadvantage of first-principles methods is that they are—despite of the
simplifications already introduced by the Born–Oppenheimer approximation and the
neglect of relativistic effects in Eq. (1)—computationally demanding and therefore
have been traditionally restricted to relatively small molecules with less that 10 atoms.
Due to the advances in computer hardware and software efficiency in the last decade,
the applicability of first-principles methods has been extended to systems with up to a
few hundred atoms (see other chapters of this book). Nevertheless, there is still a need
for simpler methods that are able to treat problems that are beyond the capabilities of
the more correct theories [2]. This is particularly true for the treatment of large
biomolecules with many hundreds to thousands of atoms, computer-aided drug
design, or the development of quantitative structure activity relationships (QSAR),
where a routine treatment of a large number of molecules is necessary. In some cases,
approximate methods have been shown to provide similar accuracy as the more
sophisticated approaches with a very small fraction of the computational effort [3]. In
addition, even if the quantitative accuracy of semiempirical methods is usually limited,
they can give insights into qualitative trends that are sometimes lost with high-level
methods (for a more philosophical discussion of this point, see a recent article by
Hoffmann [4]).
For these and other reasons, semiempirical methods have been developed as
early as in the 1930s, starting with the famous Hückel method [1]. From the mid-1960s
and so on, a vast variety of different semiempirical methods have been developed [1,5–
10]. They have been widely used for the prediction of structural, energetic, and
spectroscopic properties of molecular and solid-state systems in chemistry, biochem-
istry, biology, and pharmaceutics. The development of new semiempirical methods
and their improvement and extension of application to larger and more complex
systems have been continued until present [2,3,11].
This review gives a brief summary of the theoretical background of some of the
most popular semiempirical methods together with recent examples of their use in
modern chemical, biological, and pharmaceutical research.

2. APPROXIMATIONS
The basis for all semiempirical methods described in this chapter is the ab initio
Hartree–Fock (HF) theory [1]. Here the wave function W of an N-electron system is
approximated as a single Slater-determinant W0 of spin orbitals /. The spin orbitals
are a product of a molecular orbital (MO) u and a spin function (a or b), /a=uaa,
/a ¼ ua b.
W0 ¼ j/1 /1 /2 /2 . . . /M /M > ð5Þ
In a closed-shell system, N is an even number and all M MOs are occupied with two
electrons with a and b spin. This implies M=N/2. The molecular orbitals are expressed
as a linear combination of mzM atomic orbitals v (LCAO).
X
m
ua ¼ cla vl ð6Þ
l
Copyright © 2004 Taylor & Francis Group LLC
 By substituting W with Eq. (5), integrating, and applying the variation principle, the
Schrödinger equation (1) is converted into a system of linear equations, the Roothaan
equation [12] (recently reviewed by Zerner [13]).
FC ¼ SCe ð7Þ
where the Fock matrix F is the effective Hamilton operator, C is the matrix of the MO
coefficients cla, S is the overlap matrix, and e is a diagonal matrix including the orbital
energies. A similar equation can be constructed for open-shell systems [14]. The Fock
matrix includes all information about the quantum-chemical system, i.e., all inter-
actions that are included in the calculation. Its general ab initio formulation is the
following:
1
Flm ¼ Hlm þ Jlm
Klm
2
Xm X  
m
1 ð8Þ
¼ Hlm þ Pqr ðlmjqrÞ
ðlrjqmÞ
q r
2
Z
with Hlm ¼ vl ð1Þĥvm ð1Þdq1 ð9Þ
ZZ
1 
ðlm j qrÞ ¼ vl ð1Þvm ð1Þ v ð2Þvr dq1 dq2 ð10Þ
r12 q
X
m
Pqr ¼ 2 cqa cra ð11Þ
a

where l, m, q, and r denote AOs and Hlm are one-electron integrals representing the
expectation values of the kinetic energy operator and the electron-nuclear potential
energy operator V̂ en of Eq. (2). The (lmjqr) are two-electron repulsion integrals
representing V̂ ee, and the Pqr are elements of the density matrix P. Jlm and Klm are
the matrix representations of the so-called Coulomb and Exchange operator Ĵ and K̂,
respectively. The electronic energy [Eq. (1)] can be expressed by the eigenvalues ea
X

M
1Xm
1
Eel ¼ 2 ea
Plm Jlm
Klm ð12Þ
a
2 lm 2

Since the Fock matrix is dependent on the orbital coefficients, the Roothaan equations
have to be repeatedly solved in an iterative process, the self-consistent field (SCF)
procedure. One important step in the SCF procedure is the conversion of the general
eigenvalue equation (7) into an ordinary one by an orthogonalization transformation
[15].
Fk Ck ¼ Ck e ð13Þ
with
Fk ¼ S
1=2 FS
1=2 ð14Þ
and
Ck ¼ S1=2 C ð15Þ

1/2
S is constructed from the overlap matrix S. Solving Eq. (13) is equivalent to finding
the matrix of the eigenvectors Ck, which transforms Fk into diagonal form.
ðCk Þ þ Fk Ck ¼ e
Copyright © 2004 Taylor & Francis Group LLC
ð16Þ
 32 Bredow

The orthogonalization transformation [Eq. (14)] is also a very important consider-

ation in semiempirical calculations as will be discussed in later sections. In semi-
empirical methods, the Hartree–Fock–Roothaan approach is simplified.
1. In the construction of W0: usually, only valence electrons are treated ex-
plicitly. In some cases (Hückel, PPP), only p electrons of certain systems are
taken into account. Only a minimal atomic basis set is taken into account.
This means that H atoms are described by a 1s function, the elements Li–F
by a {2s,2p} set, the elements Na–Cl by a {3s, 3p} set, Ca, K, and Zn–Br with
{4s, 4p}, Sc–Cu with {4s, 4p, 3d}, and so on. In some cases, additional sets of
shells have been used on selected elements.
2. In the construction of Fk: a large part of the interactions is neglected,
particularly in the two-electron part (lmjqr). All integrals involving AOs
centered at more than two centers are neglected. Certain classes of integrals
are replaced by parameterized functions. This is mainly the case for the two-
center one-electron integrals Hlm that are, to a large extent, responsible for
the chemical bonding.
The above simplifications are responsible for the reduction in computational
cost of semiempirical methods compared to ab initio (HF and post-HF) or density-
functional methods which makes them a useful tool for the investigation of large
systems or the routine treatment of large numbers of systems. This statement is, to a
large extent, correct even today, despite the considerable technical improvements in
ab initio and DFT methodology of the recent years. On the same computer, the
computational time for an electronic structure calculation of a relatively small
molecule, tetracene C18H12, was compared for a semiempirical method and several
standard DFT, HF, and post-HF methods [3]. It turned out that HF and DFT
methods require about 1000 to 10 000 times more CPU time, while the factor
increases to 36 000 with a post-HF method. Future technical developments of first-
principles methods might reduce these factors, but also the efficiency of semiempirical
methods has been improved as will be shown in the next sections. The price to pay
when approximate methods are used is of course the accuracy of the calculated
properties which is, in general (but not always), inferior to that of first-principles
calculations. In this respect, it is interesting to note that recent analyses of ab initio
effective Hamilton operators [3,16] showed that the approximations and parametric
forms of semiempirical methods can at least be partially justified based on funda-
mental theory.
The various semiempirical methods can be distinguished by the way in which
these simplifications are introduced in the model. This will be shown in detail in the
following sections.

3. METHODS
3.1. Hückel Method
The most serious approximations are made in the Hückel MO (HMO) method
developed for conjugated planar hydrocarbons [1]. In the original method, the ele-
ments of the effective Fock matrix [Eq. (8)] are completely parameterized and
no molecular integral has to be calculated. Only one 2pp AO per C atom
Copyright © 2004 Taylor & Francis Group LLC
 is considered in the LCAO [Eq. (6)]. For a system with NC carbon atoms, one
gets
X
NC
/HMO
a ¼ cla Cl ð2ppÞ ð17Þ
l

The Hückel MOs /HMO

a are normalized.
X
NC
c2la ¼ 1 ð18Þ
l

HMO
The diagonal elements of the HMO ‘‘Fock’’ matrix Fll , the so-called Coulomb
integrals, are assumed to have the same value a for every carbon atom in the molecule,
HMO
and the only nonzero off-diagonal elements Flr , the resonance integrals, are those
between neighboring C atoms l and r. They are also set to the same value, b,
irrespective of the molecular structure. This parameter can be obtained from a fitting
to experimental optical spectra. Both parameters a and b have the dimension energy
and are usually given in atomic units, a.u., or Hartree, Eh. In order to convert a.u. into
the more familiar caloric or SI units, the following conversion factors have to be used
[17]: 1 a.u. u 627.5 kcal/mol u 2625 kJ/mol.
The hydrogen atoms are not taken into account. For this reason, and since only
nearest-neighbor interactions are considered, the Hückel matrices for cis- and trans-
butadiene C4H6 are identical (Fig. 1).
0 1
a b 0 0
Bb a b 0C
FHMO ðbutadieneÞ ¼ B@0 b a bA
C ð19Þ
0 0 b a
In general, the corresponding Hückel orbitals /aHMO and eigenvalues ea can be
obtained by standard diagonalization techniques for which a large number of pro-
grammed routines are available [18–20], in correspondence to the ab initio procedure
[Eq. (16)]. Due to the simple structure of the Hückel matrix, it is, however, possible to
obtain analytical expressions for the eigenvalues. In the case of conjugated chains with
NC carbon atoms, solving the secular equation jFHMO
ej=0 gives [21]
ea ¼ a
x a b


ap ð20Þ
xa ¼ 2 cos
NC þ 1

Figure 1 Numbering of C atoms in (a) cis- and (b) trans-butadiene.

Copyright © 2004 Taylor & Francis Group LLC
 34 Bredow

Since the HMO Fock matrix is not dependent on the orbital coefficients, no SCF
procedure as for ab initio methods (Sec. 2) has to be performed. In the present example
with NC = 4, the four orbital energies are x1 = 1.618b, x2 = 0.618b, x3 =
0.618b,
and x4 =
1.618b. Since the parameter b is chosen to be negative, the first energy x1
has the lowest value, and the fourth x4 has the highest value. This corresponds to the
usual convention in quantum chemistry. From these values, the orbital diagram of
butadiene can be drawn.
In Fig. 2, the two lowest MOs were occupied with two electrons of opposite spin
according to the aufbau principle. Two results can be obtained from an HMO
calculation: the excitation energies comparable to optical transitions in absorption
spectroscopy [22] and the total energy E el. The lowest HMO excitation energy of
butadiene corresponding to the transition of one electron from the highest occupied
MO (HOMO), No. 2, to the lowest unoccupied MO (LUMO), No. 3 (Fig. 2), is e3
e2
= 1.236jbj. In spectroscopy, excitation energies are usually given as reciprocal
wavelength (wave numbers, unit cm
1).
1 eLUMO
eHOMO
ðbutadieneÞ ¼ ¼ 1:236j
j ð21Þ
k hc
Here, h and c are Planck’s constant and the speed of light, respectively [23]. On the
other hand, Eq. (21) can be used to determine the semiempirical parameter b of the
HMO method if the reciprocal wavelength 1/k is taken from an accurate measurement.
In practice, b is chosen to approximate the excitation energies of a large variety of
hydrocarbons [1] as close as possible. For excitation energies, the parameter a does not
have to be specified at all and could be set to zero. It only plays a role for the calculation
of the total energy. Since the HMO theory does not contain Coulomb or Exchange
operators, the calculation of the total energy [Eq. (12)] simplifies to
X
M
E el;HMO ¼ na e a ð22Þ
a

where na is the occupation number of the ath MO. na is, in general, equal to 2 but is 1
for the HOMO of conjugated polyenes with an odd number of carbon atoms. For

Figure 2 Hückel MO diagram for butadiene derived from analytical expression (21).
Copyright © 2004 Taylor & Francis Group LLC
 butadiene, Eq. (22) gives E el,HMO (butadiene) = 4a+4.472b. A famous example of the
use of HMO total energies is the calculation of delocalization energies or resonance
energies for aromatic compounds. For the prototype aromatic molecule benzene
C6H6, the HMO energy is 6a+8b. If the molecule would consist of three separated p
systems (or, alternatively, three C2H2 molecules), the HMO energy would be 6a+6b.
Thus the stabilization energy due to delocalization of the three p orbitals is 2b (Fig. 3).
The resonance energy per p electron (REPE) has been used as a measure for the
aromaticity of molecules [24]. For a recent and comprehensive overview of the
aromaticity concept, see, for example, Refs. [25,26].
A generalization of the Hückel method to nonplanar systems comprised of
carbon and heteroatoms is the Extended Hückel Theory (EHT) [27–30]. It takes
explicitly into account all valence electrons, i.e., {1s} for H and {2s,2p} for C, N, O,
and F. Similar to the HMO method, the ‘‘Fock’’ matrix in EHT FEHT does not contain
EHT
two-electron integrals. The diagonal elements Fll are obtained from experimental
ionization potentials (IPs) where the Koopmans theorem [31] has been used.
IPa ðKoopmansÞ ¼
ea ð23Þ
The off-diagonal elements are approximated by the Wolfsberg–Helmholz formula [27]
1  
EHT
Flr ¼ KSlr Fll EHT
þ Frr
EHT
ð24Þ
2
This expression takes into account the overlap Slr between two AOs vl and vr
centered at different atoms. The atomic basis functions v are represented by Slater
functions [32],

½2fnþ1=2 n
1
frA m

vSlater ¼ rA e Y1 ðh; uÞ ð25Þ
½ð2nÞ!1=2
where f is the orbital exponent and Y is a spherical harmonic. The two-center integrals
Slr over Slater functions can be easily evaluated [32].
The overlap matrix S is also taken into account in the EHT version of the general
eigenvalue equation (7) which can be solved by applying the mentioned orthogonal-
ization transformation and matrix diagonalization techniques. Due to the independ-
ence of FEHT from the orbital coefficients, no SCF procedure has to be performed. This
is similar to HMO.
Since the overlap depends on the interatomic distance, the EHT distinguishes
between molecular conformations and it is possible to calculate equilibrium structures

Figure 3 Resonance energy of benzene: transition from a fictitious system with three
separated p bonds to the delocalized ground state.
Copyright © 2004 Taylor & Francis Group LLC
 36 Bredow

using standard minimization techniques [33]. Thus the EHT represents the most
simple all-valence electron semiempirical method. It has been successfully used by
Hoffmann et al. in applications to a vast variety of systems, and it is still frequently
used nowadays (see Sec. 6).

3.2. Pariser–Parr–Pople Method

The Hückel Theory in general gives reliable values only for the lowest excitation
energies of the HOMO ! LUMO transition of aromatic or conjugated hydrocarbons.
It cannot also distinguish between singlet and triplet excited states that are exper-
imentally known to have different luminescence characteristics. The reason for this
deficiency is the neglect of electron–electron interactions in the Hückel method. A
semiempirical p electron method that explicitly takes into account electron–electron
repulsion V̂ee in the effective Hamilton operator [Eq. (2)] is the Pariser–Parr–Pople
(PPP) method [34,35]. It has been designed for the calculation of optical absorption
spectra of aromatic hydrocarbons. Similar to the HMO theory, only C 2p p functions
are taken into account and all other atoms in the molecule are ignored.
PPP
In the evaluation of the effective PPP Fock matrix elements, Flm , the zero
differential overlap (ZDO) approximation is used.
vl ð1Þvm ð1Þdq1 ¼ 0 for lpm ð26Þ
This is a fundamental assumption that is used more or less strictly in all semiempirical
SCF MO methods. It has several important consequences.
R
1. The overlap matrix S becomes the unit matrix E (or, by integrating Eq. (26),
mA (1) mr (1) dq1=Slm=dlm is obtained.)
2. From all two-electron integrals (lm|qr), only the ‘‘diagonal’’ terms of type
(ll|qq) remain. This reduces the size dependence of semiempirical methods
from formally N4 (as is the case for HF methods) to only N2. Here lies the
main reason why semiempirical methods are able to treat very large
systems with up to N=10 000 electrons. (It has to be kept in mind that for
the PPP method, the number of electrons and the number of atomic basis
functions are identical. This is, in general, not the case for all-valence
semiempirical methods and certainly not for ab initio methods using
extended basis sets.)
At first sight, these are rather drastic approximations. However, it has been proven
that they are at least partly justified in an orthogonalized basis after a transformation
according to Eq. (14). In the orthogonal basis, most of the integrals neglected in the
ZDO approximation become smaller in absolute magnitude, and their relevance for
the total energy and excitation energy is diminished [1,3]. Recently, the fundamental
reasons for the PPP model Hamiltonian to qualitatively and semiquantitatively
reproduce spectroscopic features of conjugated polyenes have been reexamined on
the basis of high-level coupled cluster calculations [36].
The explicit form of the PPP Fock matrix [compared to the ab initio expression
(9)] is
XX
B
1
PPP
Fll ¼ Hll
PPP
þ Prr cAB
Pll cAA ð27Þ
B r
2

Copyright © 2004 Taylor & Francis Group LLC

 1
PPP
Flr ¼ Hlr
PPP

Plr cAB l at atom A; r at atom B ð28Þ
2
The integrals HPPP
lr and cAB are calculated from semiempirical formulas that contain
adjustable parameters. These are optimized in order to reproduce properties of a given
class of molecules in an optimal manner (see Sec. 4). The intra-atomic electron
repulsion integral cAA is estimated from experimentally measured ionization energies
and electron affinities (see, for example, Ref. [23]).
The PPP method is the first semiempirical method presented here where the Fock
matrix does depend on the MO coefficients C [via the density matrix elements P, see
Eq. (11)]. Therefore, the Roothaan equations (by definition due to the ZDO approx-
imation) in the orthogonal basis, Eq. (13), have to be solved in an iterative process until
self-convergence is achieved [self-consistent field (SCF) procedure]. As starting
coefficients C0, usually the orbitals of an HMO calculation are used.
Within the framework of PPP theory, it is possible to obtain excitation energies
with the Configuration Interaction (CI) method. This method is described in greater
detail in other chapters of this book. Here only a brief description is given. The PPP
ground-state wave function is a single Slater determinant [Eq. (5)]. For closed-shell
molecules with an even number N of electrons, M=N/2 MOs are doubly occupied and
also M orbitals remain unoccupied. It is now possible to construct ‘‘excited’’
determinants by exchanging one or more occupied spin orbitals [i.e., either with a
spin (/) or with b spin (/)] with unoccupied orbitals. For example, a determinant
where the occupied a spin orbital a has been substituted by the unoccupied a spin
orbital p is denoted as Wpa . An improved ground-state wave function WCI can then be
obtained by a linear combination of the original ground-state Slater determinant W0
and the modified determinants.

X
M X
M
CCI ¼ C0 C0 þ ðCpa Cpa þ Cpa Cpa Þ þ ðCpq Wpq þ : : : Þ ð29Þ
ab ab
ap abpq

The optimal coefficients C of the CI ground state are obtained by a variational

procedure. At the same time also, CI states of higher energy are obtained. In the
simplest CI expansion, only single substitutions of the type a X b and a X b are taken
into account in Eq. (29). This procedure is called single-excitation CI (SCI). Only
singlet (multiplicity of 1) and triplet (multiplicity 3) states are obtained in this way,
while the inclusion of multiple substitutions gives rise to states of multiplicity 5 and
higher. The lowest singlet state 1 CCI0 is the CI ground state, and the higher CI singlet
1 CI : : :
states are denoted by 1 CCI
1 ; C 2 ; . The energy difference Eð1 CCI 1 CI
1 Þ
Eð C0 Þ is then
comparable to the lowest excitation energy of an experimental absorption spectrum.
The PPP method is little used nowadays and has been largely superseded by more
general semiempirical methods (see the following sections). However, it is still worth to
mention since the approximations of the PPP approach are the prototype model of all
methods that were developed later.

3.3. CNDO Method

The Complete Neglect of Differential Overlap method (CNDO) of Pople et al. [8,37–39]
makes use of the ZDO approximation [Eq. (26)] for all pairs of atomic basis functions.
It treats explicitly all valence electrons (e.g., C 2s, C 2p), but neglects completely the
Copyright © 2004 Taylor & Francis Group LLC
 38 Bredow

effect of inner (core) electrons (e.g., C 1s). The CNDO Fock matrix elements therefore
reduce to
X
A XX
B
CNDO
Fll ¼ Hll
CNDO
þ Pmm cAA þ Prr cAB
m B pA r

1 ð30Þ
FlmCNDO ¼
Plm cAA
2
1
FlCNDO ¼ HlCNDO
Plr cAB ðl; m at atom A; r at atom BÞ ð31Þ
2
For symmetry reasons, the intra-atomic one-electron integrals HCNDOlm vanish. The
one-electron matrix elements Hll are subdivided into intra-atomic contributions U
and interatomic contributions due to the electron attraction VBen with other nuclei B.
X
HllCNDO
¼ Ull
B
Ven
B pA

CNDO
Hlr ¼ bAB Slr ð32Þ

cAB ¼ ðsA sA j sB sB Þ

In fact, the nuclear attraction integrals include an effective core charge Z* which is the
nuclear charge Z reduced by the number of core electrons. The intra-atomic integral
Ull contains the kinetic energy and the nuclear attraction with the nucleus where the
AO l is centered. The two-electron repulsion integrals (ll|rr) are calculated over s-
type functions invariably, and also when l or r are p-type atomic functions. These
approximate integrals are called cAB. The replacement of p functions by angular-
independent s functions is necessary in order to fulfill the requirement of rotational
invariance as discussed in Refs. [37,40]. Calculated molecular properties must be
independent from the orientation in a global coordinate system (in the absence of an
external field). For the same reason, the nuclear attraction integrals VBen are calculated
using s-type AOs only.
All two electron one-center integrals (ll|mm) are reduced to a single cAA. The two-
center one-electron integrals HCNDO
lr are set proportional to the overlap integral Slr
which is calculated over Slater-type functions (and only here not neglected according
to the ZDO assumption). The coefficient bAB is calculated either from atomic
parameters bA or orbital-dependent parameters bl.

bAB ¼ 12 ðbA þ bB Þ
or ð33Þ
blA mB ¼ ðblA þ bmB Þ
1
2

According to the Wolfsberg–Helmholz formula (24), the b parameters can be regarded

as diagonal terms of the CNDO Fock matrix.
There are two versions of CNDO, CNDO/1 and CNDO/2, which differ in the
evaluation of the intra-atomic integral Ull. In CNDO/1, it is taken from experimental
IP of the free atom [8]. In CNDO/2, a modified procedure is used [41]. In order to
compensate for deficiencies of CNDO/1 in describing long-range intermolecular
Copyright © 2004 Taylor & Francis Group LLC
 electrostatic interactions, the evaluation of VBen was modified in CNDO/2 (see Ref.
[42]).
  
Z 
Ven ðCNDO=1Þ ¼ sA  B sA
B
ð34Þ
RA
B
Ven ðCNDO=2Þ ¼ ZB cAB ð35Þ

The CNDO method is used to a lesser extent than EHT or less approximate semi-
empirical methods (see Sec. 6). The accuracy of energetic and electronic properties
obtained with CNDO is, in general, inferior to that of the methods described in the
next sections, while the computational effort of the SCF calculation is comparable.

3.4. INDO Method

The Intermediate Neglect of Differential Overlap (INDO) method, originally devel-
oped by Pople and Beveridge [8] and Pople et al. [44], uses the ZDO approximation
[Eq. (26)] only for two-center integrals. The elements of the INDO Fock operator are
therefore modified with respect to CNDO mainly by the inclusion of one-center
exchange-type integrals (lm|lm).
 X
A  XX B
1
INDO
Fll ¼ þ
CNDO
Hll Pmm ðll j mmÞ
ðlm j lmÞ þ Pmm cAB ð36Þ
m
2 B pA m
 
3 1
FlmINDO ¼ Plm ðlm j lmÞ
ðll j mmÞ ð37Þ
2 2
1
INDO
Flr ¼ Hlr
CNDO

Plr cAB ðl; m at atom A; r at atom BÞ ð38Þ
2
The one-center two-electron integrals (ll|mm) and (lm|lm) are partly calculated analyti-
cally and partly derived from atomic spectra [8]. The original INDO method gives
unsatisfying results for geometries and dissociation energies and was soon replaced by
several improved versions which are still in use nowadays, namely, MINDO/3, INDO/
S, and SINDO1. The first of these newer INDO methods is MINDO/3 (third version of
the modified INDO) by Bingham et al. [45], the successor of MINDO/1 [46] and
MINDO/2 [47]. The new idea of MINDO was to replace the time-consuming
analytical calculation of two-electron integrals cAB (e.g., using the Harris algorithm
[48]; recent algorithms for two-electron integrals over Slater orbitals can be found in
Ref. [49]) by a simple multipole expansion, suggested by Ohno [50] and Klopman [51].
1
cAB ðMINDOÞ ¼ qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ð39Þ
R2AB þ 14 ðcAA þ cBB Þ2

The calculation of two-center one-electron integrals has been modified compared to

INDO.
HMINDO
lr ¼ bAB Slr ðHll
CNDO
þ Hrr
CNDO
Þ ð40Þ
Here bAB are empirical interatomic parameters that have been optimized to minimize
the errors in heats of formation with respect to experiment of some reference com-
Copyright © 2004 Taylor & Francis Group LLC
 40 Bredow

pounds (see Sec. 4). The Pauli repulsion, which is not included in the CNDO or INDO
method, has been incorporated into the core–core potential Vnn in the total energy
calculation [Eq. (3)]. In order to obtain a balance between attractive and repulsive
terms, the analytical 1/RAB dependence has been replaced by cAB plus a correction
term. This also in part accounts for the neglected interactions of inner orbitals.
X
MINDO
Vnn ¼ ZA ZB cAB þ fAB ð41Þ
A>B


1
MINDO
fAB ¼
cAB e
aAB RAB ð42Þ
RAB

with the additional bond parameter aAB. The one-center integrals are calculated by a
method due to Oleari et al. [52]. The MINDO/3 version improved in general geom-
etries and dissociation energies compared to the original INDO methods, but also had
several failures for specific compounds.
The most frequently used INDO-type method nowadays, known as INDO/S or
ZINDO, has been developed by Zerner and Ridley [54] and Bacon and Zerner [55].
From the very beginning, it has been designed for the calculation of molecular spectra
of organic molecules and complexes containing transition metals, while its results for
structural properties are less accurate. INDO/S starts from the original INDO Fock
matrix terms [Eq. (38)] together with the analytic expression for the internuclear
repulsion Vnn. Special attention has been given to the calculation of one-center two-
electron integrals from Slater–Condon factors F and G and the evaluation of Ull from
experimental ionization energies [55]. For example, the ionization process that
removes an s electron of an atom with a {slpmdn} electronic configuration can be
expressed in terms of Ull, F, and G.

IPs ¼ Eðsl
1 pm dn Þ
Eðsl pm dn Þ

   
1 1 1 2 ð43Þ
¼
Uss
ðl
1ÞFss
m Fsp
Gsp
n Fsd
Gsd
0 0 0
6 10
0
The one-center Coulomb integrals (ll|mm)=Flm are calculated analytically while the G
integrals are taken as parameters. The IP are taken from atomic spectra. After
rearranging Eq. (43), the Uss are obtained. A special feature of INDO/S is the use of
distance-dependent Slater exponents for the calculation of two-center integrals [55].

fðRÞ ¼ a þ b=R for fðRÞ < fð0Þ ð44Þ

fðRÞ ¼ fð0Þ elsewhere ð45Þ

This procedure to some extent mimics the use of multiple-zeta basis sets in high-quality
ab initio calculations. Later, also charge-dependent orbital exponents that are more
flexible with respect to the chemical environment have been implemented in INDO/S
[56]. For transition metal atoms, one-center integrals of the general form (lm|qk) are
taken into account which do not appear in the original INDO method.
For the two-center one-electron integrals, a conventional INDO formalism is
applied. There are two sets of optimized parameter sets for INDO/S. One has been
optimized for electronic spectra and the other for molecular geometries. Therefore, in
Copyright © 2004 Taylor & Francis Group LLC
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 Though he was touched by the kindness of the good folk, there was yet
nothing the youth desired so much as to return to his kindred.

"Give me," said he, "a white horse and a white mule."

The Return to Earth

The old man bade him go to where the horses were hobbled, and there he
found what he had asked for. He also received from his host a magic piece
of iron, which would enable him to obtain whatever he desired. The rocks
even melted away at a touch of this talisman. Thus equipped, the adventurer
rode off.
"He emerged in his own country"
 Shortly afterward he emerged in his own country, where the first persons
he met were the chief and his wife, to whom he disclosed his identity, as he
was by this time very much changed. They were sceptical at first, but soon
they came to recognize him, and gave him a very cordial reception.

He married the chief's daughter, and was made head chieftain by his
father-in-law. The people built a lodge for him in the centre of the
encampment, and brought him many valuable presents of clothing and
horses. On his marriage-day the criers were sent out to tell the people that
on the following day no one must leave the village or do any work.

On the morrow all the men of the tribe went out to hunt buffaloes, and
the young chieftain accompanied them. By means of his magic piece of iron
he charmed many buffaloes, and slew more than did the others.

Now it so happened that the chief's remaining son was very jealous of
his brother-in-law. He thought his father should have given him the
chieftainship, and the honours accorded by the people to his young relative
were exceedingly galling to him. So he made up his mind to kill the youth
and destroy his beautiful white horse. But the sagacious beast told its master
that some one was plotting against his life, and, duly warned, he watched in
the stable every night.

On the occasion of a second great buffalo hunt the wicked schemer

found his opportunity. By waving his robe he scared the buffaloes and
caused them to close in on the youth and trample him to death. But when
the herd had scattered and moved away there was no trace of the young
brave or of his milk-white steed. They had returned to the Underworld.

White Feather the Giant-Killer

There once dwelt in the heart of a great forest an old man and his
grandchild. So far as he could remember, the boy had never seen any human
being but his grandfather, and though he frequently questioned the latter on
the subject of his relatives he could elicit no information from him. The
truth was that they had perished at the hands of six great giants. The nation
to which the boy belonged had wagered their children against those of the
giants that they would beat the latter in a race. Unfortunately the giants
won, the children of the rash Indians were forfeited, and all were slain with
the exception of little Chácopee, whose grandfather had taken charge of
him. The child learned to hunt and fish, and seemed quite contented and
happy.

One day the boy wandered away to the edge of a prairie, where he found
traces of an encampment. Returning, he told his grandfather of the ashes
and tent-poles he had seen, and asked for an explanation. Had his
grandfather set them there? The old man responded brusquely that there
were no ashes or tent-poles: he had merely imagined them. The boy was
sorely puzzled, but he let the matter drop, and next day he followed a
different path. Quite suddenly he heard a voice addressing him as "Wearer
of the White Feather." Now there had been a tradition in his tribe that a
mighty man would arise among them wearing a white feather and
performing prodigies of valour. But of this Chácopee as yet knew nothing,
so he could only look about him in a startled way. Close by him stood a
man, which fact was in itself sufficiently astonishing to the boy, who had
never seen any one but his grandfather; but to his further bewilderment he
perceived that the man was made of wood from the breast downward, only
the head being of flesh.

"You do not wear the white feather yet," the curious stranger resumed,
"but you will by and by. Go home and sleep. You will dream of a pipe, a
sack, and a large white feather. When you wake you will see these things by
your side. Put the feather on your head and you will become a very great
warrior. If you want proof, smoke the pipe and you will see the smoke turn
into pigeons."

He then proceeded to tell him who his parents were, and of the manner
in which they had perished, and bade him avenge their death on the giants.
To aid him in the accomplishment of this feat he gave him a magic vine
which would be invisible to the giants, and with which he must trip them up
when they ran a race with him.
 Chácopee returned home, and everything happened as the Man of Wood
had predicted. The old grandfather was greatly surprised to see a flock of
pigeons issuing from the lodge, from which Chácopee also shortly emerged,
wearing on his head a white feather. Remembering the prophecy, the old
man wept to think that he might lose his grandchild.

In Search of the Giants

Next morning Chácopee set off in search of the giants, whom he found
in a very large lodge in the centre of the forest. The giants had learned of
his approach from the 'little spirits who carry the news.' Among themselves
they mocked and scoffed at him, but outwardly they greeted him with much
civility, which, however, in nowise deceived him as to their true feelings.
Without loss of time they arranged a race between Chácopee and the
youngest giant, the winner of which was to cut off the head of the other.
Chdcopee won, with the help of his magic vine, and killed his opponent.
Next morning he appeared again, and decapitated another of his foes. This
happened on five mornings. On the sixth he set out as usual, but was met by
the Man of Wood, who informed him that on his way to the giants' lodge he
would encounter the most beautiful woman in the world.

Chácopee's Downfall

"Pay no attention to her," he said earnestly. "She is there for your

destruction. When you see her turn yourself into an elk, and you will be safe
from her wiles."

Chácopee proceeded on his way, and sure enough before long he met the
most beautiful woman in the world. Mindful of the advice he had received,
he turned himself into an elk, but, instead of passing by, the woman, who
was really the sixth giant, came up to him and reproached him with tears for
taking the form of an elk when she had travelled so far to become his wife.
Chácopee was so touched by her grief and beauty that he resumed his own
shape and endeavoured to console her with gentle words and caresses. At
last he fell asleep with his head in her lap. The beautiful woman once more
became the cruel giant, and, seizing his axe, the monster broke Chácopee's
back; then, turning him into a dog, he bade him rise and follow him. The
white feather he stuck in his own head, fancying that magic powers
accompanied the wearing of it.
"Everything happened as the Man of Wood had predicted"
 In the path of the travellers there lay a certain village in which dwelt two
young girls, the daughters of a chief. Having heard the prophecy concerning
the wearer of the white feather, each made up her mind that she would
marry him when he should appear. Therefore, when they saw a man
approaching with a white feather in his hair the elder ran to meet him,
invited him into her lodge, and soon after married him. The younger, who
was gentle and timid, took the dog into her home and treated him with great
kindness.

One day while the giant was out hunting he saw the dog casting a stone
into the water. Immediately the stone became a beaver, which the dog
caught and killed. The giant strove to emulate this feat, and was successful,
but when he went home and ordered his wife to go outside and fetch the
beaver only a stone lay by the door. Next day he saw the dog plucking a
withered branch and throwing it on the ground, where it became a deer,
which the dog slew. The Giant performed this magic feat also, but when his
wife went to the door of the lodge to fetch the deer she saw only a piece of
rotten wood. Nevertheless the giant had some success in the chase, and his
wife repaired to the home of her father to tell him what a skilful hunter her
husband was. She also spoke of the dog that lived with her sister, and his
skill in the chase.

The Transformation

The old chief suspected magic, and sent a deputation of youths and
maidens to invite his younger daughter and her dog to visit him. To the
surprise of the deputation, no dog was there, but an exceedingly handsome
warrior. But alas! Chácopee could not speak. The party set off for the home
of the old chief, where they were warmly welcomed.

It was arranged to hold a general meeting, so that the wearer of the white
feather might show his prowess and magical powers. First of all they took
the giant's pipe (which had belonged to Chácopee), and the warriors
smoked it one after the other. When it came to Chácopee's turn he signified
that the giant should precede him. The giant smoked, but to the
disappointment of the assembly nothing unusual happened. Then Chácopee
took the pipe, and as the smoke ascended it became a flock of pigeons. At
the same moment he recovered his speech, and recounted his strange
adventures to the astounded listeners. Their indignation against the giant
was unbounded, and the chief ordered that he should be given the form of a
dog and stoned to death by the people.

Chácopee gave a further proof of his right to wear the white feather.
Calling for a buffalo-hide, he cut it into little pieces and strewed it on the
prairie. Next day he summoned the braves of the tribe to a buffalo-hunt, and
at no great distance they found a magnificent herd. The pieces of hide had
become buffaloes. The people greeted this exhibition of magic art with loud
acclamations, and Chácopee's reputation was firmly established with the
tribe.

Chácopee begged the chief's permission to take his wife on a visit to his
grandfather, which was readily granted, and the old man's gratitude and
delight more than repaid them for the perils of their journey.

How the Rabbit Caught the Sun

Once upon a time the Rabbit dwelt in a lodge with no one but his
grandmother to keep him company. Every morning he went hunting very
early, but no matter how early he was he always noticed that some one with
a very long foot had been before him and had left a trail. The Rabbit
resolved to discover the identity of the hunter who forestalled him, so one
fine morning he rose even earlier than usual, in the hope of encountering
the stranger. But all to no purpose, for the mysterious one had gone, leaving
behind him, as was his wont, the trail of the long foot.

This irritated the Rabbit profoundly, and he returned to the lodge to

consult with his grandmother.

"Grandmother," he grumbled, "although I rise early every morning and

set my traps in the hope of snaring game, some one is always before me and
frightens the game away. I shall make a snare and catch him."

"Why should you do so?" replied his grandmother. "In what way has he
harmed you?"

"It is sufficient that I hate him," replied the querulous Rabbit, and
departed. He secreted himself among the bushes and waited for nightfall.
He had provided himself with a stout bowstring, which he arranged as a
trap in the place where the footprints were usually to be found. Then he
went home, but returned very early to examine his snare.

When he arrived at the spot he discovered that he had caught the

intruder, who was, indeed, no less a personage than the Sun. He ran home at
the top of his speed to acquaint his grandmother with the news. He did not
know what he had caught, so his grandmother bade him seek the forest once
more and find out. On returning he saw that the Sun was in a violent
passion.

"How dare you snare me!" he cried angrily. "Come hither and untie me
at once!"

The Rabbit advanced cautiously, and circled round him in abject terror.
At last he clucked his head and, running in, cut the bowstring which secured
the Sun with his knife. The Sun immediately soared upward, and was
quickly lost to sight. And the reason why the hair between the Rabbit's
shoulders is yellow is that he was scorched there by the great heat which
came from the Sun-god when he loosed him.

How the Rabbit Slew the Devouring Hill

In the long ago there existed a hill of ogre-like propensities which drew
people into its mouth and devoured them. The Rabbit's grandmother warned
him not to approach it upon any account.
 But the Rabbit was rash, and the very fact that he had been warned
against the vicinity made him all the more anxious to visit it. So he went to
the hill, and cried mockingly: "Pahe-Wathahuni, draw me into your mouth!
Come, devour me!"

But Pahe-Wathahuni knew the Rabbit, so he took no notice of him.

Shortly afterward a hunting-party came that way, and Pahe-Wathahuni

opened his mouth, so that they took it to be a great cavern, and entered. The
Rabbit, waiting his chance, pressed in behind them. But when he reached
Pahe-Wathahuni's stomach the monster felt that something disagreed with
him, and he vomited the Rabbit up.
"Once more the Rabbit entered, disguised as a man"
 Later in the day another hunting-party appeared, and Pahe-Wathahuni
again opened his capacious gullet. The hunters entered unwittingly, and
were devoured. And once more the Rabbit entered, disguised as a man by
magic art. This time the cannibal hill did not eject him. Imprisoned in the
monster's entrails, he saw in the distance the whitened bones of folk who
had been devoured, the still undigested bodies of others, and some who
were yet alive.

Mocking Pahe-Wathahuni, the Rabbit said: "Why do you not eat? You
should have eaten that very fat heart." And, seizing his knife, he made as if
to devour it. At this Pahe-Wathahuni set up a dismal howling; but the Rabbit
merely mocked him, and slit the heart in twain. At this the hill split asunder,
and all the folk who had been imprisoned within it went out again, stretched
their arms to the blue sky, and hailed the Rabbit as their deliverer; for it was
Pahe-Wathahuni's heart that had been sundered.

The people gathered together and said: "Let us make the Rabbit chief."
But he mocked them and told them to be gone, that all he desired was the
heap of fat the hill had concealed within its entrails, which would serve him
and his old grandmother for food for many a day. With that the Rabbit went
homeward, carrying the fat on his back, and he and his grandmother
rejoiced exceedingly and were never in want again.

CHAPTER VI: MYTHS AND LEGENDS OF THE

PAWNEES

The Pawnees, or Caddoan Indians

The Caddoan stock, the principal representatives of which are the

Pawnees, are now settled in Oklahoma and North Dakota. From the earliest
period they seem to have been cultivators of the soil, as well as hunters, and
skilled in the arts of weaving and pottery-making. They possessed an
elaborate form of religious ceremonial. The following myths well exemplify
how strongly the Pawnee was gifted with the religious sense.

The Sacred Bundle

A certain young man was very vain of his personal appearance, and
always wore the finest clothes and richest adornments he could procure.
Among other possessions he had a down feather of an eagle, which he wore
on his head when he went to war, and which possessed magical properties.
He was unmarried, and cared nothing for women, though doubtless there
was more than one maiden of the village who would not have disdained the
hand of the young hunter, for he was as brave and good-natured as he was
handsome.

One day while he was out hunting with his companions—the Indians
hunted on foot in those days—he got separated from the others, and
followed some buffaloes for a considerable distance. The animals managed
to escape, with the exception of a young cow, which had become stranded
in a mud-hole. The youth fitted an arrow to his bow, and was about to fire,
when he saw that the buffalo had vanished and only a young and pretty
woman was in sight. The hunter was rather perplexed, for he could not
understand where the animal had gone to, nor where the woman had come
from. However, he talked to the maiden, and found her so agreeable that he
proposed to marry her and return with her to his tribe. She consented to
marry him, but only on condition that they remained where they were. To
this he agreed, and gave her as a wedding gift a string of blue and white
beads he wore round his neck.

One evening when he returned home after a day's hunting he found that
his camp was gone, and all round about were the marks of many hoofs. No
trace of his wife's body could he discover, and at last, mourning her bitterly,
he returned to his tribe.
 Years elapsed, and one summer morning as he was playing the stick
game with his friends a little boy came toward him, wearing round his neck
a string of blue and white beads.

"Father," he said, "mother wants you."

The hunter was annoyed at the interruption.

"I am not your father," he replied. "Go away."

The boy went away, and the man's companions laughed at him when
they heard him addressed as 'father,' for they knew he was a woman-hater
and unmarried.

However, the boy returned in a little while. He was sent away again by
the angry hunter, but one of the players now suggested that he should
accompany the child and see what he wanted. All the time the hunter had
been wondering where he had seen the beads before. As he reflected he saw
a buffalo cow and calf running across the prairie, and suddenly he
remembered.

Taking his bow and arrows, he followed the buffaloes, whom he now
recognized as his wife and child. A long and wearisome journey they had.
The woman was angry with her husband, and dried up every creek they
came to, so that he feared he would die of thirst, but the strategy of his son
obtained food and drink for him until they arrived at the home of the
buffaloes. The big bulls, the leaders of the herd, were very angry, and
threatened to kill him. First, however, they gave him a test, telling him that
if he accomplished it he should live. Six cows, all exactly alike, were placed
in a row, and he was told that if he could point out his wife his life would be
spared. His son helped him secretly, and he succeeded. The old bulls were
surprised, and much annoyed, for they had not expected him to distinguish
his wife from the other cows. They gave him another test. He was requested
to pick out his son from among several calves. Again the young buffalo
helped him to perform the feat. Not yet satisfied, they decreed that he must
run a race. If he should win they would let him go. They chose their fastest
runners, but on the day set for the race a thin coating of ice covered the
ground, and the buffaloes could not run at all, while the young Indian ran
swiftly and steadily, and won with ease.

The Magic Feather

The chief bulls were still angry, however, and determined that they
would kill him, even though he had passed their tests. So they made him sit
on the ground, all the strongest and fiercest bulls round him. Together they
rushed at him, and in a little while his feather was seen floating in the air.
The chief bulls called on the others to stop, for they were sure that he must
be trampled to pieces by this time. But when they drew back there sat the
Indian in the centre of the circle, with his feather in his hair.

It was, in fact, his magic feather to which he owed his escape, and a
second rush which the buffaloes made had as little effect on him. Seeing
that he was possessed of magical powers, the buffaloes made the best of
matters and welcomed him into their camp, on condition that he would
bring them gifts from his tribe. This he agreed to do.

When the Indian returned with his wife and son to the village people
they found that there was no food to be had; but the buffalo-wife produced
some meat from under her robe, and they ate of it. Afterward they went
back to the herd with gifts, which pleased the buffaloes greatly. The chief
bulls, knowing that the people were in want of food, offered to return with
the hunter. His son, who also wished to return, arranged to accompany the
herd in the form of a buffalo, while his parents went ahead in human shape.
The father warned the people that they must not kill his son when they went
to hunt buffaloes, for, he said, the yellow calf would always return leading
more buffaloes.

By and by the child came to his father saying that he would no more visit
the camp in the form of a boy, as he was about to lead the herd eastward.
Ere he went he told his father that when the hunters sought the chase they
should kill the yellow calf and sacrifice it to Atius Tiráwa, tan its hide, and
wrap in the skin an ear of corn and other sacred things. Every year they
should look out for another yellow calf, sacrifice it, and keep a piece of its
fat to add to the bundle. Then when food was scarce and famine threatened
the tribe the chiefs should gather in council and pay a friendly visit to the
young buffalo, and he would tell Tiráwa of their need, so that another
yellow calf might be sent to lead the herd to the people.

When he had said this the boy left the camp. All was done as he had
ordered. Food became plentiful, and the father became a chief, greatly
respected by his people. His buffalo-wife, however, he almost forgot, and
one night she vanished. So distressed was the chief, and so remorseful for
his neglect of her, that he never recovered, but withered away and died. But
the sacred bundle was long preserved in the tribe as a magic charm to bring
the buffalo.

Their sacred bundles were most precious to the Indians, and were
guarded religiously. In times of famine they were opened by the priests with
much ceremony. The above story is given to explain the origin of that
belonging to the Pawnee tribe.

The Bear-Man

There was once a boy of the Pawnee tribe who imitated the ways of a
bear; and, indeed, he much resembled that animal. When he played with the
other boys of his village he would pretend to be a bear, and even when he
grew up he would often tell his companions laughingly that he could turn
himself into a bear whenever he liked.

His resemblance to the animal came about in this manner. Before the boy
was born his father had gone on the war-path, and at some distance from his
home had come upon a tiny bear-cub. The little creature looked at him so
wistfully and was so small and helpless that he could not pass by without
taking notice of it. So he stooped and picked it up in his arms, tied some
Indian tobacco round its neck, and said: "I know that the Great Spirit,
Tiráwa, will care for you, but I cannot go on my way without putting these
things round your neck to show that I feel kindly toward you. I hope that
the animals will take care of my son when he is born, and help him to grow
up a great and wise man." With that he went on his way.

On his return he told his wife of his encounter with the Little Bear, told
her how he had taken it in his arms and looked at it and talked to it. Now
there is an Indian superstition that a woman, before a child is born, must not
look fixedly at or think much about any animal, or the infant will resemble
it. So when the warrior's boy was born he was found to have the ways of a
bear, and to become more and more like that animal the older he grew. The
boy, quite aware of the resemblance, often went away by himself into the
forest, where he used to pray to the Bear.

The Bear-Man Slain

On one occasion, when he was quite grown up, he accompanied a war

party of the Pawnees as their chief. They travelled a considerable distance,
but ere they arrived at any village they fell into a trap prepared for them by
their enemies, the Sioux. Taken completely off their guard, the Pawnees, to
the number of about forty, were slain to a man. The part of the country in
which this incident took place was rocky and cedar-clad and harboured
many bears, and the bodies of the dead Pawnees lay in a ravine in the path
of these animals. When they came to the body of the Bear-man a she-bear
instantly recognized it as that of their benefactor, who had sacrificed
smokes to them, made songs about them, and done them many a good turn
during his lifetime. She called to her companion and begged him to do
something to bring the Bear-man to life again. The other protested that he
could do nothing. "Nevertheless," he added, "I will try. If the sun were
shining I might succeed, but when it is dark and cloudy I am powerless."

The Resuscitation of the Bear-Man

 The sun was shining but fitfully that day, however. Long intervals of
gloom succeeded each gleam of sunlight. But the two bears set about
collecting the remains of the Bear-man, who was indeed sadly mutilated,
and, lying down on his body, they worked over him with their magic
medicine till he showed signs of returning life. At length he fully regained
consciousness, and, finding himself in the presence of two bears, was at a
loss to know what had happened to him. But the animals related how they
had brought him to life, and the sight of his dead comrades lying around
him recalled what had gone before. Gratefully acknowledging the service
the bears had done him, he accompanied them to their den. He was still
very weak, and frequently fainted, but ere long he recovered his strength
and was as well as ever, only he had no hair on his head, for the Sioux had
scalped him. During his sojourn with the bears he was taught all the things
that they knew—which was a great deal, for all Indians know that the bear
is one of the wisest of animals. However, his host begged him not to regard
the wonderful things he did as the outcome of his own strength, but to give
thanks to Tiráwa, who had made the bears and had given them their wisdom
and greatness. Finally he told the Bear-man to return to his people, where
he would become a very great man, great in war and in wealth. But at the
same time he must not forget the bears, nor cease to imitate them, for on
that would depend much of his success.

"I shall look after you," he concluded. "If I die, you shall die; if I grow
old, you shall grow old along with me. This tree"—pointing to a cedar
—"shall be a protector to you. It never becomes old; it is always fresh and
beautiful, the gift of Tiráwa. And if a thunderstorm should come while you
are at home throw some cedar-wood on the fire and you will be safe."

Giving him a bear-skin cap to hide his hairless scalp, the Bear then bade
him depart.

Arrived at his home, the young man was greeted with amazement, for it
was thought that he had perished with the rest of the war party. But when he
convinced his parents that it was indeed their son who visited them, they
received him joyfully. When he had embraced his friends and had been
congratulated by them on his return, he told them of the bears, who were
waiting outside the village. Taking presents of Indian tobacco, sweet-
smelling clay, buffalo-meat, and beads, he returned to them, and again
talked with the he-bear. The latter hugged him, saying: "As my fur has
touched you, you will be great; as my hands have touched your hands, you
will be fearless; and as my mouth touches your mouth, you will be wise."
With that the bears departed.

True to his words, the animal made the Bear-man the greatest warrior of
his tribe. He was the originator of the Bear Dance, which the Pawnees still
practise. He lived to an advanced age, greatly honoured by his people.

CHAPTER VII: MYTHS AND LEGENDS

OF THE NORTHERN AND NORTH-WESTERN
INDIANS

Haida Demi-Gods

There is a curious Haida story told of the origin of certain supernatural

people, who are supposed to speak through the shamans, or medicine-men,
and of how they got their names.

Ten brothers went out to hunt with their dogs. While they were climbing
a steep rocky mountain a thick mist enveloped them, and they were
compelled to remain on the heights. By and by they made a fire, and the
youngest, who was full of mischief, cast his bow in it. When the bow was
burnt the hunters were astonished to see it on the level ground below. The
mischievous brother thereupon announced his intention of following his
weapon, and by the same means. Though the others tried hard to dissuade
him, he threw himself on the blazing fire, and was quickly consumed. His
brothers then beheld him on the plain vigorously exhorting them to follow
his example. One by one they did so, some boldly, some timorously, but all
found themselves at last on the level ground.

As the brothers travelled on they heard a wren chirping, and they saw
that one of their number had a blue hole in his heart. Farther on they found
a hawk's feather, which they tied in the hair of the youngest. They came at
length to a deserted village on the shores of an inlet, and took possession of
one of the huts. For food they ate some mussels, and having satisfied their
hunger they set out to explore the settlement. Nothing rewarded their search
but an old canoe, moss-grown and covered with nettles. When they had
removed the weeds and scraped off the moss they repaired it, and the
mischievous one who had led them into the fire made a bark bailer for it, on
which he carved the representation of a bird. Another, who had in his hair a
bunch of feathers, took a pole and jumped into the canoe. The rest followed,
and the canoe slid away from the shore. Soon they came in sight of a village
where a shaman was performing.

Attracted by the noise and the glow of the fire, the warrior at the bow
stepped ashore and advanced to see what was going on. "Now," he heard
the shaman say, "the chief Supernatural-being-who-keeps-the-bow-off is
coming ashore." The Indian was ashamed to hear himself thus mistakenly,
as he thought, referred to as a supernatural being, and returned to the canoe.
The next one advanced to the village. "Chief Hawk-hole is coming ashore,"
said the shaman. The Indian saw the blue hole at his heart, and he also was
ashamed, and returned to his brothers. The third was named Supernatural-
being-on-whom-the-daylight-rests, the fourth Supernatural-being-on-the-
water-on-whom-is-sunshine, the fifth Supernatural-puffin-on-the-water, the
sixth Hawk-with-one-feather-sticking-out-of-the-water, the seventh
Wearing-clouds-around-his-neck, the eighth Supernatural-being-with-the-
big-eyes, the ninth Supernatural-being-lying-on-his-back-in-the-canoe, and
the eldest, and last, Supernatural-being-half-of-whose-words-are-raven.
Each as he heard his name pronounced returned to the canoe. When they
had all heard the shaman, and were assembled once more, the eldest brother
said, "We have indeed become supernatural people," which was quite true,
for by burning themselves in the fire they had reached the Land of Souls.[1]
 [1] This myth would appear to explain the fancied resemblance between
smoke and the shadowy or vaporous substance of which spirits or ghosts
are supposed to be composed.

The Supernatural Sister

The ten brothers floated round the coast till they reached another village.
Here they took on board a woman whose arms had been accidentally
burned by her husband, who mistook them for the arms of some one
embracing his wife. The woman was severely burned and was in great
distress. The supernatural brothers made a crack in the bottom of the canoe
and told the woman to place her hands in it. Her wounds were immediately
healed. They called her their sister, and seated her in the canoe to bail out
the water. When they came to the Djū, the stream near which dwelt Fine-
weather-woman,[2] the latter came and talked to them, repeating the names
which the shaman had given them, and calling their sister Supernatural-
woman-who-does-the-bailing.

[2] See page 316.

"Paddle to the island you see in the distance," she added. "The wizard
who lives there is he who paints those who are to become supernatural
beings. Go to him and he will paint you. Dance four nights in your canoe
and you will be finished."

They did as she bade them, and the wizard dressed them in a manner
becoming to their position as supernatural beings. He gave them dancing
hats, dancing skirts, and puffin-beak rattles, and drew a cloud over the
outside of their canoe.
The Birth of Sîñ

The Haida of British Columbia and the Queen Charlotte Islands possess
a striking myth relating to the incarnation of the Sky-god, their principal
deity. The daughter of a certain chief went one day to dig in the beach. After
she had worked some time she dug up a cockle-shell. She was about to
throw it to one side when she thought she heard a sound coming from it like
that of a child crying. Examining the shell, she found a small baby inside.
She carried it home and wrapped it in a warm covering, and tended it so
carefully that it grew rapidly and soon began to walk.

She was sitting beside the child one day when he made a movement with
his hand as if imitating the drawing of a bowstring, so to please him she
took a copper bracelet from her arm and hammered it into the shape of a
bow, which she strung and gave him along with two arrows. He was
delighted with the tiny weapon, and immediately set out to hunt small game
with it. Every day he returned to his foster-mother with some trophy of his
skill. One day it was a goose, another a woodpecker, and another a blue jay.

One morning he awoke to find himself and his mother in a fine new
house, with gorgeous door-posts splendidly carved and illuminated in rich
reds, blues, and greens. The carpenter who had raised this fine building
married his mother, and was very kind to him. He took the boy down to the
sea-shore, and caused him to sit with his face looking toward the expanse of
the Pacific. And so long as the lad looked across the boundless blue there
was fair weather.

His father used to go fishing, and one day Sîñ—for such was the boy's
name—expressed a wish to accompany him. They obtained devil-fish for
bait, and proceeded to the fishing-ground, where the lad instructed his
father to pronounce certain magical formulæ, the result of which was that
their fishing-line was violently agitated and their canoe pulled round an
adjacent island three times. When the disturbance stopped at last they pulled
in the line and dragged out a monster covered with piles of halibut.

One day Sîñ went out wearing a wren-skin. His mother beheld him rise
in stature until he soared above her and brooded like a bank of shining
clouds over the ocean. Then he descended and donned the skin of a blue jay.
Again he rose over the sea, and shone resplendently. Once more he soared
upward, wearing the skin of a woodpecker, and the waves reflected a colour
as of fire.

Then he said: "Mother, I shall see you no more. I am going away from
you. When the sky looks like my face painted by my father there will be no
wind. Then the fishing will be good."

His mother bade him farewell, sadly, yet with the proud knowledge that
she had nurtured a divinity. But her sorrow increased when her husband
intimated that it was time for him to depart as well. Her supernatural son
and husband, however, left her a portion of their power. For when she sits
by the inlet and loosens her robe the wind scurries down between the banks
and the waves are ruffled with tempest; and the more she loosens the
garment the greater is the storm. They call her in the Indian tongue Fine-
weather-woman. But she dwells mostly in the winds, and when the cold
morning airs draw up from the sea landward she makes an offering of
feathers to her glorious son. The feathers are flakes of snow, and they serve
to remind him that the world is weary for a glimpse of his golden face.

Master-Carpenter and Southeast

A Haida myth relates how Master-carpenter, a supernatural being, went

to war with South-east (the south-east wind) at Sqa-i, the town lying
farthest south on the Queen Charlotte Islands. The south-east wind is
particularly rude and boisterous on that coast, and it was with the intention
of punishing him for his violence that Master-carpenter challenged him.
First of all, however, he set about building a canoe for himself. The first one
he made split, and he was obliged to throw it away. The second also split,
notwithstanding the fact that he had made it stouter than the other. Another
and another he built, making each one stronger than the last, but every
attempt ended in failure, and at last, exceedingly vexed at his unskilfulness,
he was on the point of giving the task up. He would have done so, indeed,
but for the intervention of Greatest Fool. Hitherto Master-carpenter had
been trying to form two canoes from one log by means of wedges. Greatest
Fool stood watching him for a time, amused at his clumsiness, and finally
showed him that he ought to use bent wedges. And though he was perhaps
the last person from whom Master-carpenter might expect to learn anything,
the unsuccessful builder of canoes adopted the suggestion, with the happiest
results. When at length he was satisfied that he had made a good canoe he
let it down into the water, and sailed off in search of South-east.
 "He seized hold of the hair"

By and by he floated right down to his enemy's abode, and when he

judged himself to be above it he rose in the canoe and flung out a challenge.
There was no reply. Again he called, and this time a rapid current began to
float past him, bearing on its surface a quantity of seaweed. The shrewd
Master-carpenter fancied he saw the matted hair of his enemy floating
among the seaweed. He seized hold of it, and after it came South-east. The
latter in a great passion began to call on his nephews to help him. The first
to be summoned was Red-storm-cloud. Immediately a deep red suffused the
sky. Then the stormy tints died away, and the wind rose with a harsh
murmur. When this wind had reached its full strength another was
summoned, Taker-off-of-the-tree-tops. The blast increased to a hurricane,
and the tree-tops were blown off and carried away and fell thickly about the
canoe, where Master-carpenter was making use of his magic arts to protect
himself. Again another wind was called up, Pebble-rattler, who set the
stones and sand flying about as he shrieked in answer to the summons.
Maker-of-the-thick-sea-mist came next, the spirit of the fog which strikes
terror into the hearts of those at sea, and he was followed by a numerous
band of other nephews, each more to be dreaded than the last. Finally Tidal-
wave came and covered Master-carpenter with water, so that he was obliged
to give in. Relinquishing his hold on South-east, he managed to struggle to
the shore. It was said by some that South-east died, but the shamans, who
ought to know, say that he returned to his own place.

South-east's mother was named To-morrow, and the Indians say that if
they utter that word they will have bad weather, for South-east does not like
to hear his mother's name used by any one else.

The Beaver and the Porcupine

This is the tale of a feud between the beavers and the porcupines. Beaver
had laid in a plentiful store of food, but Porcupine had failed to do so, and
one day when the former was out hunting the latter went to his lodge and
stole his provision. When Beaver returned he found that his food was gone,
and he questioned Porcupine about the matter.

"Did you steal my food?" he asked.

 "No," answered Porcupine. "One cannot steal food from supernatural
beings, and you and I both possess supernatural powers."

Of course this was mere bluff on the part of Porcupine, and it in nowise
deceived his companion.

"You stole my food!" said Beaver angrily, and he tried to seize Porcupine
with his teeth. But the sharp spines of the latter disconcerted him, though he
was not easily repulsed. For a time he fought furiously, but at length he was
forced to retreat, with his face covered with quills from his spiny adversary.
His friends and relatives greeted him sympathetically. His father summoned
all the Beaver People, told them of the injuries his son had received, and
bade them avenge the honour of their clan. The people at once repaired to
the abode of Porcupine, who, from the fancied security of his lodge, heaped
insults and abuse on them. The indignant Beaver People pulled his house
down about his ears, seized him, and carried him, in spite of his threats and
protests, to a desolate island, where they left him to starve.

It seemed to Porcupine that he had not long to live. Nothing grew on the
island save two trees, neither of which was edible, and there was no other
food within reach. He called loudly to his friends to come to his assistance,
but there was no answer. In vain he summoned all the animals who were
related to him. His cries never reached them.

When he had quite given up hope he fancied he heard something

whisper to him: "Call upon Cold-weather, call upon North-wind." At first he
did not understand, but thought his imagination must be playing tricks with
him. Again the voice whispered to him: "Sing North songs, and you will be
saved." Wondering much, but with hope rising in his breast, Porcupine did
as he was bidden, and raised his voice in the North songs. "Let the cold
weather come," he sang, "let the water be smooth."

The Finding of Porcupine

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