Concepts and Experimental Protocols of Modelling and Informatics in Drug Design Om Silakari Full Chapter

Concepts and Experimental Protocols
of Modelling and Informatics in Drug

Design Om Silakari
Visit to download the full and correct content document:
https://ebookmass.com/product/concepts-and-experimental-protocols-of-modelling-an
d-informatics-in-drug-design-om-silakari/
Concepts and Experimental
Protocols of Modelling and
Informatics in Drug Design
Concepts and Experimental
Protocols of Modelling and
Informatics in Drug Design
Om Silakari
Department of Pharmaceutical Sciences and Drug Research,
Punjabi University, Patiala, India
Pankaj Kumar Singh

Department of Chemistry and Pharmacy, University of Sassari,
Sassari, Italy
Academic Press is an imprint of Elsevier
125 London Wall, London EC2Y 5AS, United Kingdom
525 B Street, Suite 1650, San Diego, CA 92101, United States
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
Copyright © 2021 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
including photocopying, recording, or any information storage and retrieval system, without permission in writing from the
publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our
arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found
at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may
be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any
information, methods, compounds, or experiments described herein. In using such information or methods they should be
mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any
injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or
operation of any methods, products, instructions, or ideas contained in the material herein.
British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
ISBN: 978-0-12-820546-4
For Information on all Academic Press publications

visit our website at https://www.elsevier.com/books-and-journals
Publisher: Stacy Masucci

Senior Acquisitions Editor: Rafael E. Teixeira
Editorial Project Manager: Sam W. Young
Production Project Manager: Niranjan Bhaskaran
Senior Cover Designer: Mark Rogers
Typeset by MPS Limited, Chennai, India
Contents
Preface................................................................................................................ xiii
Acknowledgment ................................................................................................... xv
Chapter 1: Fundamentals of molecular modeling ...................................................... 1

1.1 Molecular modeling ............................................................................................. 1
1.2 Molecular representation...................................................................................... 1
1.2.1 Cartesian coordinate ................................................................................... 2
1.2.2 Polar coordinate ......................................................................................... 3
1.2.3 Internal coordinate...................................................................................... 3
1.3 Computer graphics ............................................................................................... 3
1.4 Molecular models................................................................................................. 4
1.4.1 CPK models ............................................................................................... 4
1.4.2 Dreiding models ......................................................................................... 5
1.4.3 Computer models ....................................................................................... 6
1.5 Molecular surfaces ............................................................................................... 7
1.5.1 Van der Waals surface (VWS) ................................................................... 8
1.5.2 Solvent accessible surface .......................................................................... 8
1.5.3 Solvent excluded surface ............................................................................ 9
1.5.4 Charged partial surface area (CPSA) ........................................................ 10
1.6 Workstations....................................................................................................... 11
1.6.1 GPU hardware .......................................................................................... 11
1.7 Principles of molecular modeling...................................................................... 12
1.7.1 Molecular mechanics ................................................................................ 12
1.7.2 Molecular dynamics ................................................................................. 18
1.7.3 Quantum mechanics ................................................................................. 22
References .................................................................................................................. 25
Chapter 2: QSAR: Descriptor calculations, model generation,

validation and their application ............................................................ 29
2.1 Introduction ...................................................................................................... 29
v
vi Contents
2.2 Fundamental principle of QSAR ..................................................................... 31

2.3 QSAR methodology ......................................................................................... 32
2.3.1 Data preparation ..................................................................................... 34
2.3.2 Data analysis .......................................................................................... 37
2.3.3 Validation ............................................................................................... 39
2.4 Descriptor calculations for QSAR models ...................................................... 41
2.4.1 Types of QSAR descriptors .................................................................... 41
2.5 Development of Hansch models and their validation ..................................... 45
2.5.1 General guidelines for derivation of Hansch QSAR model ..................... 46
2.6 QSAR model generation using Free Wilson approach ................................... 47
2.6.1 Limitations.............................................................................................. 48
2.7 QSAR model generation using mixed approach ............................................. 48
2.8 3D QSAR analyses........................................................................................... 49
2.8.1 Comparative molecular field analysis (CoMFA) ..................................... 49
2.8.2 Comparative molecular similarity indices analysis, (CoMSIA) ............... 52
2.9 Conventional QSAR versus 3D-QSAR ........................................................... 54
2.10 Conclusion........................................................................................................ 54
References .................................................................................................................. 61
Chapter 3: Small molecule databases: A collection of promising

bioactive molecules .............................................................................. 65
3.1 Introduction ........................................................................................................ 65
3.2 BindingDB.......................................................................................................... 65
3.2.1 Description ............................................................................................... 66
3.2.2 Details ...................................................................................................... 66
3.3 ChEBI ................................................................................................................. 68
3.3.1 Description ............................................................................................... 69
3.3.2 Details ...................................................................................................... 69
3.4 ChemSpider ........................................................................................................ 72
3.4.1 Description ............................................................................................... 72
3.5 ChEMBL ............................................................................................................ 73
3.5.1 Description ............................................................................................... 74
3.6 ZINC................................................................................................................... 77
3.6.1 Description ............................................................................................... 77
3.6.2 Details ...................................................................................................... 78
3.7 PubChem ............................................................................................................ 79
3.7.1 Description ............................................................................................... 81
3.8 DrugBank ........................................................................................................... 82
3.8.1 Description ............................................................................................... 83
References .................................................................................................................. 86
Contents vii
Chapter 4: Database exploration: Selection and analysis of

target protein structures ..................................................................... 89
4.1 Introduction ........................................................................................................ 89
4.2 Protein databases ................................................................................................ 89
4.2.1 UniProt: the Universal Protein knowledgebase ......................................... 89
4.2.2 Research Collaboratory for Structural Bioinformatics
Protein Data Bank (RCSB PDB) .............................................................. 95
4.2.3 Binding database .................................................................................... 100
4.2.4 Therapeutic target database .................................................................... 101
References ................................................................................................................ 104
Chapter 5: Homology modeling: Developing 3D structures of target

proteins missing in databases ..............................................................107
5.1 Introduction ...................................................................................................... 107
5.2 Methodology of homology modeling .............................................................. 110
5.2.1 Template recognition and initial alignment ............................................ 111
5.2.2 Alignment correction .............................................................................. 113
5.2.3 Step 3: Backbone building ..................................................................... 113
5.2.4 Loop modeling ....................................................................................... 114
5.2.5 Side-chain modeling ............................................................................... 116
5.2.6 Ligand modeling .................................................................................... 116
5.2.7 Model optimization ................................................................................ 116
5.2.8 Model validation .................................................................................... 117
5.3 Software for homology modeling .................................................................... 118
5.3.1 Robetta ................................................................................................... 118
5.3.2 Modeller ................................................................................................. 119
5.3.3 3D-JURY ............................................................................................... 120
5.3.4 Swiss-model ........................................................................................... 120
5.4 Conclusion........................................................................................................ 121
References ................................................................................................................ 126
Chapter 6: Molecular docking analysis: Basic technique to predict

drug-receptor interactions ...................................................................131
6.1 Introduction: what is molecular docking? ....................................................... 131
6.2 Theory of docking ............................................................................................ 132
6.2.1 Sampling algorithms............................................................................... 132
6.2.2 Scoring functions ................................................................................... 135
6.3 Types of molecular docking ............................................................................ 137
6.3.1 Rigid docking: rigid ligand and rigid receptor docking .......................... 137
6.3.2 Constrained docking: flexible ligand and rigid receptor ......................... 137
viii Contents
6.3.3 Flexible docking: flexible ligand and flexible receptor docking ............. 138
6.4 Standard methodology for molecular docking ................................................ 139
6.5 Softwares available for molecular docking ..................................................... 143
6.6 Conclusion........................................................................................................ 145
References ................................................................................................................ 152
Chapter 7: Molecular dynamic simulations: Technique to analyze real-time

interactions of drug-receptor complexes ...............................................157
7.1 Introduction ...................................................................................................... 157
7.2 Principles of MD simulations .......................................................................... 158
7.2.1 Definitions.............................................................................................. 158
7.2.2 Calculating averages from a MD simulation .......................................... 159
7.2.3 Classical mechanics................................................................................ 160
7.2.4 Algorithms ............................................................................................. 163
7.3 Steps of MD simulations.................................................................................. 165
7.3.1 Initialization ........................................................................................... 165
7.3.2 Energy minimization .............................................................................. 167
7.3.3 Heating the simulation system ................................................................ 168
7.3.4 Equilibration at a constant temperature .................................................. 168
7.3.5 Production stage of MD trajectory (NVE ensemble) .............................. 168
7.4 Applications of MD simulations in drug discovery ........................................ 168
7.4.1 Identifying cryptic and allosteric binding sites ....................................... 169
7.4.2 Improving the computational identification of
small-molecule binders ........................................................................... 169
7.4.3 Advanced free-energy calculations using MD simulations ..................... 170
7.5 MD simulations: Current limitations ............................................................... 172
References ................................................................................................................ 177
Chapter 8: Water mapping: Analysis of binding site spaces

to enhance binding .............................................................................179
8.1 Introduction ...................................................................................................... 179
8.2 Thermodynamics .............................................................................................. 181
8.3 Predicting location and nature of water molecule: To be or
not to be replaced? ........................................................................................... 183
8.4 Strategies to identify cavity “waters” .............................................................. 187
8.4.1 Molecular docking.................................................................................. 187
8.4.2 Molecular dynamics ............................................................................... 189
8.4.3 Free energy calculations ......................................................................... 190
8.5 Loopholes and limitations................................................................................ 192
Contents ix
8.6 Conclusion........................................................................................................ 193

References ................................................................................................................ 197
Chapter 9: Ligand-based pharmacophore modeling: A technique utilized for

virtual screening of commercial databases ...........................................203
9.1 Introduction ...................................................................................................... 203
9.2 Methodology of pharmacophore modeling or mapping.................................. 205
9.2.1 Input: Data set preparation and conformational search ........................... 205
9.2.2 Conformational search............................................................................ 206
9.2.3 Feature extraction ................................................................................... 207
9.2.4 Pattern identification .............................................................................. 208
9.2.5 Scoring of the model .............................................................................. 209
9.2.6 Validation of pharmacophore ................................................................. 210
9.2.7 Applications of pharmacophore modeling .............................................. 211
9.3 In process determinants for quality pharmacophore modeling....................... 213
9.3.1 Molecular alignments ............................................................................. 213
9.3.2 Handling flexibility ................................................................................ 214
9.3.3 Alignment algorithms ............................................................................. 214
9.3.4 Key aspects of scoring and optimization ................................................ 215
9.4 Automated pharmacophore generation methods ............................................. 216
9.4.1 Geometry- and feature-based methods.................................................... 216
9.4.2 Field-based methods ............................................................................... 225
9.4.3 Pharmacophore fingerprints .................................................................... 226
9.4.4 ChemX/Chem Diverse, PharmPrint, OSPPREYS,
3D keys, Tuplets .................................................................................... 226
9.4.5 Other methods ........................................................................................ 227
9.5 Conclusion........................................................................................................ 230
References ................................................................................................................ 232
Chapter 10: Fragment based drug design: Connecting small substructures

for a bioactive lead .........................................................................235
10.1 Introduction .................................................................................................... 235
10.2 General strategy for fragment based drug design ......................................... 236
10.2.1 Techniques for finding fragments ....................................................... 236
10.2.2 Converting fragments into hits and leads ............................................ 239
10.2.3 Hit identification and validation.......................................................... 241
10.3 Recent advancements in FBDD techniques .................................................. 241
10.3.1 Fragment-based molecular evolutionary approach .............................. 242
10.3.2 Construction and deconstruction approach .......................................... 243
10.3.3 Computational functional group mapping ........................................... 243
x Contents
10.3.4 Multitasking computational model approach....................................... 244

10.4 Limitations...................................................................................................... 245
10.5 Conclusion...................................................................................................... 246
References ................................................................................................................ 251
Chapter 11: Scaffold hopping: An approach to improve the existing

pharmacological profile of NCEs ......................................................255
11.1 Introduction .................................................................................................... 255
11.2 Computational approaches of scaffold hopping ............................................ 256
11.2.1 Pharmacophore searching ................................................................... 257
11.2.2 Recombination of ligand fragments .................................................... 258
11.2.3 Molecular similarity method ............................................................... 260
11.3 Conclusion...................................................................................................... 261
References ................................................................................................................ 264
Chapter 12: Hotspot and binding site prediction: Strategy to target

protein protein interactions ............................................................267
12.1 Introduction .................................................................................................... 267
12.2 Protein protein binding sites ........................................................................ 268
12.3 Types of protein protein interaction regions ............................................... 269
12.4 Computational prediction of protein binding sites........................................ 269
12.4.1 Protein protein docking ..................................................................... 269
12.4.2 Binding site prediction based on the protein sequence ........................ 271
12.4.3 Binding site prediction based on the protein structure ........................ 271
12.4.4 Energy-based methods ........................................................................ 274
12.5 Hot-spot residues at protein interfaces .......................................................... 275
12.6 Prediction of hot spots in protein protein interactions ................................ 276
12.6.1 Hot-spot prediction based on the sequence ......................................... 276
12.6.2 Hot-spot prediction based on the structure .......................................... 276
12.6.3 Hot-spot prediction based on the unbound protein structure ............... 277
12.7 Conclusion...................................................................................................... 278
References ................................................................................................................ 281
Chapter 13: In-silico SNP analysis: An aid to identify novel potential

deleterious SNPs in drug targets ......................................................285
13.1 Introduction .................................................................................................... 285
13.2 Sequence-based approaches to SNP analysis ................................................ 286
13.3 Structure-based approaches to SNP analysis................................................. 286
13.4 Sequence-based prediction tools.................................................................... 287
Contents xi
13.4.1 SIFT ................................................................................................... 287

13.4.2 MAPP ................................................................................................. 288
13.4.3 PANTHER .......................................................................................... 288
13.4.4 Parepro ............................................................................................... 289
13.4.5 PhD-SNP ............................................................................................ 289
13.4.6 SNPs&GO .......................................................................................... 289
13.5 Structure-based prediction tools .................................................................... 290
13.5.1 PolyPhen............................................................................................. 290
13.5.2 SNPs3D .............................................................................................. 290
13.5.3 LS-SNP............................................................................................... 291
13.5.4 SNPeffect ........................................................................................... 292
13.5.5 SNAP.................................................................................................. 292
13.5.6 PMUT ................................................................................................. 293
13.5.7 SAPRED............................................................................................. 293
13.5.8 MutPred .............................................................................................. 294
13.5.9 MuD ................................................................................................... 294
13.6 Conclusion...................................................................................................... 295
References ................................................................................................................ 297
Chapter 14: ADMET tools: Prediction and assessment of chemical ADMET

properties of NCEs .........................................................................299
14.1 Introduction .................................................................................................... 299
14.2 Prediction of physicochemical properties...................................................... 301
14.2.1 Solubility and solubilization ............................................................... 301
14.2.2 Permeability and active transporters ................................................... 302
14.2.3 Hydrogen bonding .............................................................................. 302
14.2.4 Ionization constant (or dissociation constant)...................................... 303
14.2.5 Lipophilicity ....................................................................................... 303
14.3 Prediction of ADME and related properties.................................................. 304
14.3.1 Absorption.......................................................................................... 305
14.3.2 Bioavailability .................................................................................... 306
14.3.3 Blood brain barrier penetration ......................................................... 306
14.3.4 Transporters ....................................................................................... 307
14.3.5 Dermal and ocular penetration ........................................................... 309
14.3.6 Plasma-protein binding ....................................................................... 309
14.3.7 Volume of distribution ....................................................................... 309
14.3.8 Clearance ........................................................................................... 310
14.3.9 Metabolism ........................................................................................ 310
14.3.10 Toxicity .............................................................................................. 312
14.4 Computational tools for ADMET prediction ................................................ 314
14.5 Conclusion...................................................................................................... 315
References ................................................................................................................ 318
xii Contents
Chapter 15: Cheminformatic tools: Identify suitable synthesis procedures

to realize designed molecules ...........................................................321
15.1 Introduction .................................................................................................... 321
15.2 Strategies for computer assisted prediction of synthetic schemes ................ 322
15.2.1 Template library-based ....................................................................... 322
15.2.2 Template-free ..................................................................................... 322
15.2.3 Focused template application .............................................................. 323
15.3 Approaches to validate selected synthetic route ........................................... 324
15.3.1 Classifying reaction feasibility ............................................................ 324
15.3.2 Predicting mechanistic steps ............................................................... 325
15.3.3 Ranking templates .............................................................................. 325
15.3.4 Ranking products ................................................................................ 325
15.3.5 Generating products ............................................................................ 325
15.4 Tools developed so-far................................................................................... 326
15.5 Conclusion...................................................................................................... 330
References ................................................................................................................ 330
Chapter 16: Statistical methods and parameters: Tools to generate and

evaluate theoretical in silico models .................................................333
16.1 Introduction .................................................................................................... 333
16.2 Data analysis methods.................................................................................... 334
16.2.1 Principal components analysis (PCA) ................................................. 334
16.2.2 Cluster analysis ................................................................................... 334
16.3 Regression methods........................................................................................ 334
16.3.1 Simple regression analysis .................................................................. 335
16.3.2 Multiple linear regressions .................................................................. 336
16.3.3 Stepwise multiple linear regression ..................................................... 336
16.3.4 Principal components regression (PCR) .............................................. 336
16.3.5 Partial least square regression analysis................................................ 337
16.3.6 Genetic function approximation (GFA)............................................... 340
16.3.7 Genetic partial least squares (G/PLS) ................................................. 340
16.4 Evaluation of in silico models ....................................................................... 341
16.4.1 Internal validation ............................................................................... 341
16.4.2 External validation .............................................................................. 345
16.4.3 Virtual screening validation ................................................................ 348
16.5 Conclusion...................................................................................................... 348
References ................................................................................................................ 349
Glossary .............................................................................................................351
Index ..................................................................................................................367
Preface
The main reason for proposing a new book in the field of CADD is increasing focus of
educational institution towards molecular modeling as a key and rational approach for drug
discovery. Research scholars, undergrad students and sometimes even teachers of drug
design and medicinal chemistry do not readily find books to guide their research ideas and
CADD-based experiments. Students as well as teachers usually gain theoretical knowledge
via various books available in the market but they lack proper experimental application of
these tools. Most of the books available in libraries focus on the theoretical concepts of
computer-aided drug design and use of molecular modeling in general. Thorough
examination of such books disappoint scholars and teachers as they do not provide any
insight into the actual application of these theoretical concepts into solving research
problems. Even the books providing discussion about different softwares utilized in in-silico
analysis fail in providing the clear guidelines to a “lay-man”, to utilize them. Therefore, we
wanted to write a book that reflects on the issues faced by researchers in the practical
application of concepts of CADD, rather than a theory book on definitions and explanations
of CADD. This book will be a handbook for practical applications of different in-silico
tools available today along with various information about hardware as well as list of
softwares commonly employed in CAMM.
Of all the current trends in medicinal chemistry, CADD based studies are most common
and rationale approach. More importantly the correct utilization of such tools is important
to obtain reliable results and therefore the user, which could be anyone from an undergrad
student to a doctoral fellow, should be well-versed about the application of such tools and
techniques. Additionally, experience in solving the problem arising during performing an
analysis is necessary. We were greatly intrigued by the vast application offered by this field
and believe that researchers would benefit more from a book that provide sample exercises
in each chapter to guide an end user in practising a CAMM exercise on any and every
software package/online servers. Users can re-perform the given exercises which will help
them in understanding the correct interpretation in context of their study.
xiii
xiv Preface
Such a book can facilitate the actual application of multiple CAMM based approaches
employed in the process of drug designing. Each user who utilize a CAMM based tools do
not actually have set standard to compare his/her obtained results. This book will provide
users with a standard protocol and results which can be utilized to validate their own results
and will aid in building confidence over the obtained results.
We also kept in mind that information regarding the general principles associated with the
basic concepts of molecular modeling is also imperative for the book to become a
significant piece of literature. We aimed at an approach that would make sense and appeal
to today’s research scholars. Thus we incorporated a subsection in each chapter that
specifically understated the update in the current knowledge in each tools and technique of
this field. To avoid complexity in discussions, we have provided graphical representations
of general protocol followed in each in-silico technique for drug designing. We have
deliberately omitted detailed discussion of obscure theoretical principles and have only
focussed on simple explanations and information on how to utilize computers and artificial
intelligence in the process of drug design. This book will also help the readers in
understanding the utility of freely available software tools for the purpose of understanding
the complex process of identification of a suitable drug for a pathological condition and
their development.
Each chapter will discuss the basic protocols utilized in the process of lead identification to
optimization and finally prediction of its mechanism of action. The book will provide a set
exercise which could be utilized by the researcher to optimize and validate the tool
employed by him. Additionally this book will provide good number of exercises to UG
students (B.Pharm, B.Tech (bioinformatics), BSc (bioinformatics), BSc (biotechnology),
BSc (biochemistry)) and PG students (M.Pharm (all streams), MSc (bioinformatics)),
valuable to train them for their practical applications. Thus, this book may serve well to the
beginners of molecular modeling. It may be followed by the graduate student to gain basic
knowledge about the tools and route exercises of molecular modeling.
Acknowledgment
Authors would like to thank Dr. Bhawna Vyas, Research Associate, Department of
Chemistry, Punjabi University, Patiala, Ms. Shalki Choudhary, Senior Research Fellow,
DPSDR, Punjabi University, Patiala and Ms. Himanshu Verma, Senior Research Fellow,
DPSDR, Punjabi University, Patiala, for their providing assistance and suggestions while
compiling this book. Authors are also indebted to the supportive, and at the same time
critical, faculty members of the department of Pharmaceutical Sciences and Drug Research.
Authors would also like to acknowledge the support and guidance from Samuel Young,
Editorial Project Manager, Elsevier and Rafael Teixeira, Acquisitions Editor, Cancer
Research/Oncology, Medical Informatics/Bioinformatics, Systems Biology and Biostatistics,
Elsevier, along with other members of the editorial team at Elsevier. Finally, the time spent
on the preparation of this book was made available only with the forbearance of our
families, friends, and research groups, and we thank all of them for their patience and
understanding.
A special mention to Prof. Mario Sechi, Department of Chemistry and Pharmacy,
University of Sassari, Sassari, Italy, for his constant guidance, support and for providing an
excellent environment during the execution of this work.
xv
CHAPTER 1
Fundamentals of molecular modeling
1.1 Molecular modeling

Molecular modeling describes the generation, representation and/or manipulation of 3-D
structure of chemical and biological molecules, along with determination of physicochemical
properties that can help to interpret structural activity relationship (SAR) of the biological
molecules. Molecular modeling provides scientist with five major types of information.
a. The 3D structure of molecules
b. The chemical and physical characteristics of the molecules
c. Comparison of structure of a molecule with other different molecules
d. Visualization of complexes formed between different molecules/macromolecules
e. Prediction about how new related molecules might look
For the analysis of exponentially increasing data obtained through the introduction of automated
whole genome and protein sequencing techniques, in the early 2000s, the field of bioinformatics
emerged rapidly [1]. From the pioneering laborious mapping and comparison of protein and
gene sequences in molecular biology, via an intense phase, which to a large extent can be
viewed as ‘database mining’ and the development of efficient computer based algorithms, into a
science of its own, which today has reached a high level of maturity and sophistication. Tools
in bioinformatics are nowadays used with great success in structural biology, computational
chemistry, genetics, molecular biology, pharmaceutical industry, pharmacology and more. In
this chapter, a brief outline of the basics of molecular modeling is given, focusing on the
interfaces between medicinal chemistry, pharmacology, computational chemistry, informatics,
artificial intelligence and machine learning. This includes molecular representations, computer
graphics, molecular surfaces and their principles such as molecular mechanics/quantum
mechanics/molecular dynamics [2]. The aim is to provide a brief introduction to a vast and
rapidly growing field. In subsequent chapters, more specialized drug designing tools and
techniques are presented, that build upon the foundations given herein.
1.2 Molecular representation

One of the most basic and usually ignored component of molecular modeling study is
representation of the molecules. Since the beginning of the molecular modeling studies
Concepts and Experimental Protocols of Modelling and Informatics in Drug Design.

DOI: https://doi.org/10.1016/B978-0-12-820546-4.00001-5 1
© 2021 Elsevier Inc. All rights reserved.
2 Chapter 1
there have been several refinement in the methods utilized to represent molecules in in-
silico studies. To represent 3D structure of a molecule and electronic properties associated
with it, certain coordinate systems are required. Following coordinate system are generally
used for molecular representation.
1.2.1 Cartesian coordinate
In Cartesian coordinate system, two perpendicular lines are chosen in the plane and the
coordinates of a point are taken to be assigned as distances to the lines (Fig. 1.1A).
Similarly for 3-D representation of molecules, three perpendicular planes are chosen and
three coordinates of a point are assigned as distances to each of the planes (Fig. 1.1B).
Depending on the direction and order of the coordinate axis the system may be a right hand
or a left hand system (Fig. 1.1C) [3]. This coordinate system is important to understand the
orientation of the molecules in molecular space on computer as in Fig. 1.1B and 1.1C.
orientations of chair conformations of cyclohexane are different as their Cartesian
coordinate are different.
Figure 1.1
Coordinate system for representation of a molecule: Cartesian (A) 2D, (B) & (C) 3D and (D)
polar coordinate.
Fundamentals of molecular modeling 3
1.2.2 Polar coordinate
In this system, a point is chosen as the pole and a ray from this point is taken as
the polar axis. For a given angle θ, there is a single line through the pole whose
angle with the polar axis is θ. Then there is unique point on this line whose signed
distance from the origin is r for given number r. For a given pair of coordinates
(r, θ) there is a single point, but any point is represented by many pairs of
coordinates. For example, (r, θ), (r, θ 1 2π) and (-r, θ 1 π) are all polar coordinates
for the same point (Fig. 1.1D) [1].
1.2.3 Internal coordinate
A more chemically intuitive way of writing the coordinates is to use the internal
coordinates of a molecule (i.e. bond lengths, bond angles and torsion angles). Internal
coordinates are usually written as a Z-matrix [1]. Here is an example of a Z-matrix, for
ethene (C2H4):
Atom number Atom type Distance (Å) Bond angle ( ) Torsion angle ( )
1 C
2 C 1 1.31
3 H 1 1.07 2 121.5
4 H 1 1.07 2 121.5 3 180.0
5 H 2 1.07 1 121.5 3 180.0
6 H 2 1.07 1 121.5 4 180.0
The first line of the Z-matrix defines atom number 1 (carbon). Atom 2 is also a
carbon atom, and is at a distance of 1.31 Å from atom 1 (the approximate length of
a carbon-carbon double bond). The third column defines the atom to which the
distance in column 4 refers, i.e. atom 3 (a hydrogen) is 1.07 Å from atom 1 (the
length of the C-H bond). Similarly the atom numbers in columns 5 and 7 define
which atoms are involved in the bond angle and torsion angle (values given in
columns 6 and 8 respectively). So, for example, atom number 6 is a hydrogen. It is
1.07 Å from atom 2, the bond angle involves atoms 6-2-1, and the torsion angle is
for atoms 6-2-14. All the torsion angles are 180 , showing that the molecule is
planar. This system of coordinate is required to generate unique conformation of a
molecular system on computer screen.
1.3 Computer graphics

Computer graphics display are either vector or raster. Raster images, also known as
bitmaps, are comprised of individual pixels of color. Each color pixel contributes to the
4 Chapter 1
overall image. Raster images might be compared to pointillist paintings, which are
composed with a series of individually-colored dots of paint. Each paint dot in a pointillist
painting might represent a single pixel in a raster image. When viewed as an individual dot,
it’s just a color; but when viewed as a whole, the colored dots make up a vivid and detailed
painting. The pixels in a raster image work in the same manner, which provides rich details
and pixel-by-pixel editing. Unlike raster graphics, which are comprised of colored pixels
arranged to display an image, vector graphics are made up of paths, each with a
mathematical formula (vector) that tells the path how it is shaped and what color it is
bordered with or filled by. Since mathematical formulas dictate how the image is rendered,
vector images retain their appearance regardless of size. They can be scaled infinitely.
Vector images can be created and edited in programs such as Illustrator, CorelDraw, and
InkScape [4].
On vector displays the lines making up the image are traced on the face of the CRT. The
lines are continuous strokes and appear very straight and smooth. However only lines and
dots can be drawn on vector systems. Filled areas such as molecular surfaces, must be
represented by many closely spaced lines or dots, which adds greatly to the complexity of
the image. On raster displays, the CRT is repeatedly horizontally scanned, as on a television
screen. The image is made up of discrete pixels. Lines can appear jagged, depending on the
resolution of the CRT being used. Because of the pixels method used in raster system, filled
areas are more readily drawn on these systems than on vector systems [5].
1.4 Molecular models

The simplest types of models are CPK, dreiding models and computer models, which
provide a better way to represent molecules.
1.4.1 CPK models
CPK models are physical models in which a color coded molecular model assembly kit is
provided for representing organic molecular structures (Fig. 1.2) [6]. These models consist
of shapes comprising two basic and complementary construction units capable of being
interlocked. The basic construction units are color coded plastic tubes which can be coupled
to second basic construction units, representing the bonds between adjacent atoms. The
second basic construction units are color coded coupling spheres, according to the valency
of the atoms to be joined, the center of said coupling sphere represent atom centers. These
coupling spheres have radial arms substantially located on the surface of a sphere with the
center of the coupling unit being the center of the sphere. These units are made up of
plastic and are of two types, one type adapted for planar-trigonal coupling of three said
tubes separated by angles of about 120 and the other type adapted for tetrahedral coupling
Figure 1.2
CPK model representation of quinazoline molecule.
of four said tubes separated by angles of about 109 . Said first and second construction
units are capable of being joined together and held immobile by friction by having said
radial arms and/or the cavities of said tubes tapered so that skeletal models of complex
organic macromolecules may be assembled such that the distance between the centers of
two directly connected coupling means represents the distance between joined atoms [7].
These models give a good representation of the shape of a molecule. They can be
manipulated to produce various conformations of the molecule. But they cannot be used to
present electronic properties of molecules and they cannot be superimposed upon one
another to compare molecular conformation and shape. The bond lengths and angles cannot
be adjusted in these models.
1.4.2 Dreiding models
Dreiding models are physical models that use thin metal or plastic rods to represent
bonds [8]. Bond lengths and angles are fixed, although rotations around bonds can be easily
done. One can also demonstrate the ready conversion of one boat form into another and
then stop halfway between the two and preserve the twist form. Selection of appropriate
balls and use of rubber tubing connectors to form double bonds and C3-C4 cycloalkanes
permits construction of numerous interesting cis and trans olefins, optically active allenes,
and small ring-compounds, in some of which optical isomerism is superimposed on
geometrical isomerism. However, they give a poor representation of molecular volume and
cannot be used to show electronic properties. Depending on the complexity of the model,
they could possibly be superimposed upon one another for comparison of molecular
conformation (Fig. 1.3).
6 Chapter 1
Figure 1.3
Dreiding model representation of quinazoline molecule.
Figure 1.4
Computer model representation of ligand protein complex.
1.4.3 Computer models
Computer models can be used to draw a virtually limitless variety of molecular

representations from stick figures to molecular surfaces (Fig. 1.4). Computer graphics
models can also very readily be used to represent electronic properties of molecules. These
models can be easily superimposed and accurately constructed using any bond lengths,
angles and torsion angles. Elements are color coded and can easily be recognized on the
basis of color assignment to that particular element (Fig. 1.5).
Figure 1.5
Filled color coded computer model representation of ligand.
A disadvantage of computer models is that they are not physical, three dimensional models.
Thus computer molecular modeling tools portray images in a way that seems three
dimensional. Initially the models were drawn on cathode ray tubes (CRTs) using special
purpose computer hardware. In CRTs the images were limited to two dimension. The third
dimension was realized by rapidly displaying slightly different two dimensional images. In
this method, time was used as a parameter to represent third Cartesian dimension. This
technique is referred to as real-time graphics. Another technique used to give graphics a
three dimensional look involved drawing “in front” parts of image more brightly than parts
which are “in back”. More updated computer graphic systems such as PS350 and the silicon
graphics IRIS work station allowed to combine the techniques of real-time graphics,
stereographics and intensity depth cuing to produce a 3-D image with multiple colors.
1.5 Molecular surfaces

Molecular surface is a fundamental aspect of a structure as it is through the complementarity
of shape and chemistry of the surface that molecules interact with each other. The molecular
surface is defined as ‘the surface in contact with a probe sphere while the sphere rolls over
the surface of the molecule. More recently the increasing power of a raster graphics system
allows more complex images to be viewed interactively and this has led to the development
of many techniques for representing solid molecular surfaces (Fig. 1.6).
In modeling of a macromolecule such as protein, DNA, RNA etc. and small molecules with
biological significance, each constituent atom is considered as a simple sphere with its Van
der Waals radius. The visualization or simulations of these overlapping balls can be done
by surface mesh generation technique, where the shape quality of these overlapping balls
has a strong influence on simulation accuracy [9]. There are mainly three type of molecular
8 Chapter 1
Figure 1.6
Representation of different molecular surfaces.
surfaces that plays important role in drug designing process such as van der waals surface
(VWS), solvent-accessible surface (SAS) and solvent excluded surface (SES).
1.5.1 Van der Waals surface (VWS)
VWS simply refer to the union of all possible overlapping balls. The interactions of these
surfaces are important in various chemical and biological processes such as formation of a
tertiary structure of biopolymer, electron tunneling in protein crystals etc. The probable role
of weak VWS interactions on reaction dynamics is an issue of great concern [10]. Usually,
for the macromolecules such as proteins and nucleic acid, VWS may be buried within the
interior of the molecule. van der waal Surface bound molecules are held together by weak
attractive forces like dispersive, electrostatic, charge transfer and hydrogen bond interaction
between closed shell atoms or molecules, and molecules bound to each other by these type
of attractive forces possess low dissociation energies. The understanding of both reactive
and non-reactive dynamics in VWS complexes requires detailed information on potential
energies [11]. The VW radii of each sphere varies slightly with its covalent bonding
environment and these radii are needed for the evaluation of protein volume, interior
packing and also the packing at the protein-water interface [12].
1.5.2 Solvent accessible surface
The solvent accessible surface can be recognized as the surface created by the center of the
solvent that is regarded as a rigid sphere, when it rolls around the van der Waals surface.
This term was initially coined by Richard and Lee, when going through a study on
protein interactions [13]. They were interested in analysing the interaction of protein
with the solvent molecules to determine the hydrophobicity and folding of proteins. In
order to obtain molecular surface that a solvent could access, a probe sphere is made to
roll over the van der Waal surface, and the traces of center of the probe sphere best
describe the SAS [14]. SAS has become a common thread for most of the researchers
especially in the case of the non-polar molecules, as the free energy of aqueous solvent
is proportional to SAS, which in turn proportional to the number of solvent molecules
that are in contact to the solute molecule. Thus, SAS is a central quantity in several
solvation models used in molecular mechanics (MM) [15]. This surface can be used to
determine the amino acid environment energy which depends on an accurate and rapid
estimation of SAS. It can also be used to compute partition coefficient (logP), which is
an important parameter extensively used in studying the structural-biological activity.
Further, in molecular modeling study, the interactions of the compound with non-polar
phase can be determined by utilizing SAS information both in vitro and in vivo [16].
The constructive solid operation geometry operation can be applied for the
representation of SAS and the implicit functions underlying the molecular surface can
be defined through some steps as displayed in Fig. 1.7. The first step is sign change of
these functions, then identification of atoms and definition of function used for the map
evaluation of molecular surface and eventually the clustering of atoms. Function fSAS
(.) can be computed by adding the contribution of those atoms [(C i,Ri)]iεIζI that belong
to the sphere of center x and radius 2r, which is a constructive solid geometry
operation [17].
1.5.3 Solvent excluded surface
Solvent excluded surface (SES) is one of the most popular surface definitions in the
field of biophysics and molecular biology. It is divided into two parts i.e. contact
surface and the reentrant surface. The contact surface, as a part of the van der Waals
surface of each atom is accessible to a probe sphere of a given radius. The reentrant
surface is described as the inward-facing part of the probe sphere, while in contact with
more than one atom [13]. Later, Connolly developed the mathematical representation of
the SES for arbitrary biomolecules in terms of concave patches, saddle patches, and
concex spherical patches [18]. Among these regions, the convex contact surface
segment of the van der Waals surface possess direct contact to the solvent surrounding
the system, and the concave re-entrant surface segment in which solvent sphere has
contact with two or more atoms spheres of the structure. Cannolly representation of SES
is standard tool in molecular modeling that allows quantitative and qualitative
comparison of molecules [14]. The actual representation of solvent excluded surfaces is
displayed in Fig. 1.8.
10 Chapter 1
Figure 1.7
Steps involved defining implicit functions underlying molecular surface.
1.5.4 Charged partial surface area (CPSA)
The physical and chemical properties of charged partial surfaces (CPSAs) play important
role in specificity and selective interactions of ligand with protein. CPSAs were developed
to get the information about the molecular structure that in turn help in determining the
intermolecular interactions for QSAR. Practically, it is useful to ascertain the toxicity and
give description of local and global electrophilicity in non-covalent interactions. CPSA
descriptors have been used in distinguishing the antagonist and agonist that bind to estrogen
receptors. These descriptors also have utility in determining partial charge and
conformational changes [19]. Charged partial surfaces like hydrophilic and hydrophobic
surface area have their utility in various phenomenon related to protein adsorption. Usually,
absorption from hydrophobic surfaces is more effective than hydrophilic surface. Not only
the adsorption, but also some of the protein exchange processes occurs with more ease over
the hydrophobic surfaces than that of hydrophilic surfaces. There is a strong correlation of
Figure 1.8
Representation of molecular/solvent-excluded surface.
target selectivity with physical and chemical properties of these surfaces [20]. The
modulation in hydrophobic surface can be achieved by some of the factors, one of them is
temperature. Temperature, as one of the factor to induce exposure of hydrophobic surface
was identified by studying its effect on the chaperone activity of α-crystallin [21].
1.6 Workstations
Usually vector systems are preferred by molecular modelers because of their speed and high
quality of line drawing. Since these vector systems use special purpose hardware, they have
been more expensive than raster systems and are used as display devices separate from the
host computer which being used to store and modify molecular coordinates. However,
nowadays new computer graphic workstations have been introduced, which include raster
systems having a computer with full operating system and mass storage facility integrated
with the graphic display.
1.6.1 GPU hardware
The general purpose graphics processing unit (GPU) computational resource is very fast and
has also become very popular. It is strongly dependent on the hardware. Many computers
have GPU boards that are used mainly for graphics. To utilize the GPU for an application
program, we must uninstall the GPU graphics driver software and install CUDA, a
computer language for use with GPU. Most of the GPU-MD programs adopt CUDA for
12 Chapter 1
GPU computations. The slot number of each GPU board in the computer must be explicitly
indicated in CUDA. Every year, new GPU hardware has appear in the market with updated
CUDA version. The GPU program should be tuned up for each GPU, since the performance
of GPU programs depends on the balance of the number of GPU cores and memory-band
width. In contrast to CPUs, which are used for all application programs, the application of
GPU is quite limited. This means that the GPU is used only when the GPU programs are
available.
GPU computing is particularly suitable to run molecular dynamics simulation programs like
AMBER, Gromacs, NAMD and psygene-G/myPresto. Some of these GPU programs are
freely available. However, one of the most serious problems for end users is how to set up
the GPU machine for these MD programs. The other problem is that the system size for the
GPU computation must be larger than the minimum size that is determined by the program.
Since most GPU programs adopt a space-decomposition method for parallel computing, the
system must be decomposed into sub systems. This means that the MD of a small system
(like a single molecule) is not suitable for GPU computing.
1.7 Principles of molecular modeling

Modeling of molecules for understanding various types of molecular phenomenon related to
chemistry, biochemistry, biophysics, molecular biology, drug discovery and drug design,
pharmacogenomics, pharmacology etc. is based on calculation of different kinds of energy
associated with a molecular system. A molecular system is associated with three types of
energies i.e. potential energy, kinetic energy and quantum energy. Calculation and
application of these energies depend upon the type of work to be executed in problems
which are under consideration. Different fundamental principles have been employed to
calculate these three different kinds of molecular energies. Potential energy, kinetic energy
and quantum energy can be calculated by applying the concepts of molecular mechanics
(MM), Molecular Dynamics (MD) and Quantum Mechanics (QM) respectively. Now brief
account about these three concepts are discussed in next sections.
1.7.1 Molecular mechanics
Molecular mechanics treats the molecule as collection of atoms held together by spring.
This assumption is made to apply Newtonian’s mechanics (Huck’s law of mechanics) for
calculating potential energy of molecular system by considering atoms held together by
elastic or harmonic forces. These forces can be described by potential energy functions of
structural features (internal coordinates) like bond-length, bond-angles torsional angle and
non-bonded interactions of a molecule. Non-bonded atoms (greater than two bonds apart)
interact through van der Waals attraction, steric repulsion, and electrostatic attraction/
repulsion. Any deviation from the normal ideal values of internal coordinates while we are
drawing molecules on computer screen, accompanies with strain and leads to increase in the
potential energy. For example ideal value of bond angle of sp3 hybridized carbon in
methane is 109 28v. Deviation from this value leads to angle strain and subsequent
increase in potential energy of methane molecules. Thus every molecular system
experiences different kind of strain viz. bond strain, angle stain torsional strain and strain
due to non-bonding interactions which are contributors of the potential energy of
conformation of that molecular system. The combination of these potential energy functions
is known as ‘force field’ which can be defined as it is a set of rule to parameterize
potential energy functions of molecules. Fig. 1.9 displayed these different kind of strains
along with the formulas used to calculate corresponding energy contributions for potential
Figure 1.9
Components of potential energy in force field arise from different kind of strains produced in a
molecule of four atoms.
14 Chapter 1
energy of conformation in FF. Thus, the energy, E or Etotal of the molecules in the force
field arise due to deviations from ‘ideal’ structural features and can be approximated by a
sum of strain derived energies contributed by these deviation. This can be expressed in the
most general form as
Etotal 5 Es 1 Eb 1 EðWÞ 1 Enb 1 (1.1)
where,
Es 5 energy of a bond being stretched or compressed from its natural bond length;
Eb 5 energy of bending bond angles from their natural values
E(W) 5 torsional energy due to twisting about bonds
Enb5energy of the non-bonded interactions;
Etotal 5 Differences in energy between real molecule and a hypothetical molecule where
all structural values like bond angles, bond length, dihedral angle are exactly at their
ideal value.
The objective of molecular mechanics is to predict the energy associated with a given
conformation of a molecule. However, molecular mechanics energies have no meaning as
absolute quantities. Only differences in energy between two or more conformations have
meaning. MM models predict the energy of a molecule as a function of its conformation.
This allows predictions firstly for the equilibrium geometries and transition states and
secondly for relative energies between conformers or between different molecules.
Different kinds of force-fields have been developed over the years. Some include additional
energy terms that describe other kinds of deformations. Some force-fields account for
coupling between bending and stretching in adjacent bonds in order to improve the
accuracy of the mechanical model [22].
1.7.1.1 Energy minimization

The energy of a system can be calculated by using the molecular mechanics force field.
Most often one is interested in determining minimum energy structures. This can be done
by finding the coordinates at which the first derivatives of the potential function equals to
zero. There are numerous algorithms available for this geometry optimization. The simplest
and most straight-forward of these is the method of steepest descent. In steepest descent we
move down the gradient in a direction parallel to the net force. Steepest descent lead
directly to the nearest local minimum by following a path that is determined by moving
from previous value to a new value by some constant k times the direction in which the
energy is decreasing.
Another method is conjugate gradient method, unlike steepest descent, it utilizes
information from the previous gradients along with the current gradient to locate the
minimum. Conjugate gradient methods take the second search direction to be a linear
combination of the current gradients and the previous one. Conjugate gradient methods are
more efficient than steepest descent and require fewer energy evaluations and gradient
calculations. Conjugate gradient methods can also induce large changes in the coordinates
while searching for a minimum but the convergence characteristics are better than with
steepest descent.
Next method is the newton-raphson procedure, it is a powerful, convergent minimization
procedure. In the newton-raphson algorithm, one needs to have the second derivative matrix
available. This method is based on the assumption that the energy is quadratically
dependent i.e., it behaves like a classical spring. If the energy function were quadratic, the
increments x would lead directly to the minimum in one step. This is of course almost
never the case for the potential surface of complex biomolecules. Newton Raphson methods
do not need to do linear interpolations like conjugate gradient, so energy evaluations can be
speeded up by a factor of about 23.
The best compromise is to use the method of fletcher and powell. This algorithm combines
the advantages of steepest descent with newton-raphson and requires only the first
derivatives, but builds up the second derivatives by successive approximations. This method
is both quadratically convergent and efficient [23].
1.7.1.2 Classes of force field methods

Class I Methods: Higher order terms and cross terms. Higher accuracy, used for small or
medium sized molecules. Examples: Allinger’s MM14, EFF, and CFF.
Class II Methods: For very large molecules (e.g., proteins). Made cheaper by using only
quadratic Taylor expansions and neglecting cross terms. Examples: AMBER, CHARMM,
GROMOS, etc. Made even cheaper by using “united atoms.”
1.7.1.3 List of some important common force fields

AMBER: Assisted model building refinement, it is designated for the simulation of
peptide and nucleic acid [24].
CHARMm: Chemistry at Harvard Macromolecular Mechanics. It is used to model
macromolecular structure a protein [25].
CFF92: Consistent force field. Designated for accurate definitions of both small and
large molecules [26].
CVFF: Consistent valence force field. It is parameterized to reproduce peptide and
proteins properties [26].
ESFF: Extensible systematic force field. It is rule based force field, which is currently
under development. The goal of this force field is to provide the widest possible
coverage [27].
Another random document with
no related content on Scribd:
called the West Canada Creek, falls down a deep ravine over successive
ledges of rock, in six small cascades of great beauty. The highest is only
fifty feet high. The sides of the ravine are precipitous, and covered with the
beautiful foliage of numerous trees. Among them are many evergreen trees
—of these I remarked the stately white pine, which grows over one hundred
feet high and perfectly straight; the red pine, with its dark green leaves, and
yellow cones; the black spruce and the lofty birch. The rocks are slate and
transition lime stone of the silurian series, abounding with petrifaction, of
which many are perfect trilobites. Quartz crystals are also found here in
great beauty and profusion. This place has been the scene of some tragic
events—one of them most pitiable. A young girl sat out upon a pleasure
tour, accompanied by her mother, father, and affianced husband. They came
to this place, no warning spirit pressing them back, no drear omen warning
them away, and no dream or presentment checking their steps. Gaily they
descended the stairs, and clambered the rocks—the lover with the hand of
his betrothed in his; the father and mother behind. Being thus led along, did
not accord with her playful spirit, and telling him she could take care of
herself, she in an evil moment withdrew her hand. His charge to be careful
was answered by smiling asseverations of her sure-footedness; he turned
with another admonition and she was gone! Where is she? He looks in
every direction. She has hid herself in play; he calls; no answer but the
torrents roar; she has rejoined her parents; he turns towards them and sees
them quietly reposing together upon a rock. His pallid look—his wildness,
as rooted to the spot, he gazes upon them, tells them the tale of woe, soon
bitterly confirmed by her pretty bonnet of straw, which was at that moment
whirled past their feet. Oh, the agony of those hearts as they stood beside
that dark torrent, away from all help, and powerless to save their beloved
one. The guide was despatched to the village for help, but not until three
days after was she found a mile below; her tender form having been thus far
carried over rocks and whirlpools.
Another family party came to view these scenes. A tender girl of eleven
years was for security consigned to the valet’s arms. One false step plunged
him into the torrent—he struggled to the shore, but the parent’s pretty
fondling was lost to them in life. The body was the next day found.
As I stood upon the slippery rock, while these events were floating
through my memory, their scenes pointed out to me by the guide; the place
lost all its beauty, and the dashing torrent seemed some huge monster,
seeking whom he might suck beneath his horrid depths. I grew nervous, and
much to my companions surprise, begged him to return. He, rejoicing in the
fresh country air, and released from the city’s dust, ran over the rocks with,
to me, an alarming quickness, and I turned to depart. Why these beloved
ones should be thus snatched away from their fond relatives; taken from
their homes to find their death in this wild spot, is to us unknown. He who
commanded this, has purposes, to us unscrutable; perhaps it was to read a
lesson to those who hear the tale, to teach them the uncertain hold they have
upon life, and all its pleasures, and to fear that power which can in an
unlooked for moment, bear them from life to eternity. There are hundreds
every season who stand upon this spot, and hear this story, and the heart
which is not affected by it must be as the hearts of the petrified animals
around them.
We spent several days here, riding and walking among the romantic
scenery.
The village of Trenton Falls is a small one, containing a few shops, and
cottages and two churches, one of which is quite pretty. The ride towards
Utica is very beautiful. The ground descends on each side to the Mohawk
valley, and while our road wound down this side, we had the whole slope of
the other side before our eyes, covered with orchards and fields, and dotted
with villages. The town of Clinton with Hamilton college, stands upon
elevated ground, while, below, at the river’s brink is spread the city of
Utica. Here we spent a day looking about its streets and shops. The ground
slopes down to the river, near which are the business streets, while most of
the dwelling houses are upon the more airy and elevated portion of the city.
Genessee street is a fine wide avenue leading up the hill, lined upon each
side with shops, hotels, churches, libraries, museums, &c. The canal is here
crossed by a pretty bridge. The houses were substantially built, surrounded,
many of them, by gardens, and appeared very comfortable residences. The
business part of the city show rows of well built ware-houses, and were
filled with people and carts passing to and fro, as if their trade was an active
one and their city thriving. The Erie canal has brought much trade to this
place, which now is one of the most flourishing inland towns in the State.
The canal boats, stages, and rail trains which are constantly arriving and
departing give a stirring appearance to the place. Religion, education, and
literature, engage the attention of the inhabitants who support sixteen
churches, and many seminaries and literary institutions. The population in
1835, was 10,183, to which now of course, several thousands must be
added. It is situated in Oneida County, which was selected by the celebrated
Baron Steuben as his retreat, and here he was buried.
June 21st.—We left Utica to-day in the three o’clock train for Auburn.
About four miles from the city we passed a small town called
Whitesborough, a pretty place, with two churches, an academy, and a
building called the Oneida Institute. There is also here a manual labor
school. A large unfinished building just outside of Utica, we learned was to
be a lunatic asylum, calculated to accommodate one thousand patients—
God pity them.
Several pretty towns lay upon our route: as Rome, Manlius, Canastola,
etc. Sweet retreats from the confusion of a city without the solitude of the
country. The canal and railroad which run through or near these towns
present facilities for trade or travelling. Rome is a place of considerable
importance, containing five churches, a court house, academy, several shops
and dwellings. The population, five years since, amounted to 4,800. When
arrived at Syracuse we drove up to a large good looking stone building
bearing the name of Syracuse House. There we stopped to take tea. This
place is sixty miles from Utica: enjoys considerable trade, but is still in its
teens, having arisen since the canal passed through that part of the country.
The Oswego canal joins the Erie here, which, with the salt works near,
brings them much business. The population is 7,000. We observed in
passing through it, several good churches, a pretty court house, substantial
ware houses, numerous shops and dwellings, with a lyceum and high
school, so that it would seem the inhabitants ought to be wealthy, refined,
and well educated. The salt springs are at Salina, one mile and a half from
Syracuse, where there are eighty manufactories of this material. These salt
springs flow from beds of slate, in some places two hundred feet thick.
Among the layers are masses of vermicular rock, whose interstices are
supposed once to have been filled with salt. In this region of country are
extensive gypsum beds; water lime is also found in profusion. Sandstone,
generally old red, and lime-stones, are the prevailing formations of the
county.
It was a beautiful evening when we left Syracuse. The sky, every where
of a clear deep blue, paled gradually as it approached the west, where it was
lost in a rich golden glow. The spires of the town behind us, reflected this
brilliant hue, and the country as we passed, looked like one of Turner’s one
colored pictures. Onondaga lake with the pretty village reposing upon its
shore, and the rich fields around it, were all touched with this golden pencil.
The fields were strewn with salt vats, where the salt was undergoing
evaporation, which were covered with low sheds, probably taken off in the
morning, as it was now late Saturday afternoon, and this might have been to
protect them from the weather. It was quite dark when we reached Auburn.
We left the cars at the railroad depot, and were provided with carriages to
the American Hotel. Here, large commodious bed rooms, and luxurious
mattresses, received your weary friends. I lingered a while to write you the
events of the day, but must now hasten to bid you—adieu.
Sunday, June 22d.—This morning we visited the first presbyterian

church, a large handsome edifice of brick. The pulpit was neat, and the seats
and backs of the pews comfortably lined with horse hair. From Mr. Lathrop,
the clergyman, we heard a very good discourse. The baptist and several
other churches struck us as very neat and tasteful. The episcopal is in the
gothic style, the interior lined with oak, and containing a handsome
monument of Bishop Hobart, who died in this place. The hotels are showy
handsome buildings, particularly the Auburn House, and the American,
where we have taken up our quarters. This last is built of grey limestone
from that neighborhood, and is surrounded by two rows of piazzas
supported by handsome pillars. Opposite to it is the court house, quite a
little palace in appearance. It is in the Parthenon form with a portico and
high pillars, with the questionable addition of a large dome. From the
cupola of an hotel, we obtained a charming view of this beautiful town and
its environs. ‘A palace and a prison on each hand,’ I exclaimed as I glanced
around, for behind was the grand court house, and in front arose the gloomy
walls and towers of our famous State Prison. We saw from here the
Theological Seminary, several handsome churches, hotels, elegant private
dwellings, and streets of shops; while the outside of the circle presented a
charming and varied range of fields, and hills, and groves and streams. It
seemed indeed the loveliest village of the plain around, and I expressed my
surprise at seeing so large and well built a town ‘so far off.’ My companion
told me it was too near the commencement of our journey to be astonished
yet, I had Rochester, and Buffalo, and Cincinnati to see. This town has a
population of nearly 7,000, I do not know exactly, but refer you to the
Gazetteers. Those of our friends whom we visited gave the place a fine
character for good society, and told us they enjoyed all the conveniences
and elegances of life, with good pastors and good books. In twenty-four
hours any thing can reach them from New York. The prison presents an
imposing appearance. It is built of dark stone with gothic ornaments, and
consist of first, a high wall enclosing a large square, in the centre of which,
rises a massive pile of building surmounted by a cupola. This building is
arranged on three sides of a square, the centre 276, the other 242 feet long.
In this are the eating rooms, hospital, chapel, and cells. The work shops are
erected against the wall leaving a space for the keeper to walk around and
gaze upon them through holes for the purpose, himself unseen. It is a dismal
life these poor creatures lead, not only encarcerated from the world, but
confined alone, and forbidden even to speak to a fellow prisoner when they
meet at table or in the shops. They pass the life of La Trappe monks, except
that it is against their will. At table they sit in rows with their faces one way,
so that they cannot even see each other. However, this solitary and silent
existence is said to be the best and most successful method of restraining
and reforming the unhappy convict. In solitude they have time for
reflection, and silence prevents corruption from their fellow criminals. They
have religious instruction, which has converted several. I cannot but think it
a very efficient arrangement. The guilty man is stopped in his mad career,
and solitude, silence, and time for reflection, and religious counsel, are
blessings placed in his path. In the mean while his bodily wants are
attended to, he is supplied with nutritious food, well ventillated rooms, with
nurses and physicians. He is obliged to work, and the fruits of his labor go
to defray the prison expenses. We saw carriages, shoes, cabinet-ware, and
various other articles made by them, offered for sale in the shops of the
village.[1]
L E T T E R I V.
June 23d, 1840.
Dear E.—At ten o’clock, we entered the stage coach for Rochester, 70
miles distant. Among our passengers were two whom we had found
extremely interesting, while journeying from Utica here—a clergyman of
Massachusetts and his daughter. The Rev. N. T——r, was about seventy,
but extremely active, and very cheerful. His conversation was instructive
and agreeable and of course in a pious vein, for he had occupied the pulpit
47 years, as had his ancestors for 230 years back. There was such simplicity
of heart about him, such piety, and kindness of manner, joined with elevated
thought and deep learning that we lent a charmed ear to his discourse,
during the whole day.
Our route lay through an exquisitely beautiful country, covered with
cultivated farms and varied with pretty lakes and towns. The first lake we
saw was Cayuga lake. It is from one to four miles broad, and thirty-eight
long. It is a bright sheet of water, lying in a deep valley and from its surface
its shores gently rise, covered with a fine farming country. We crossed the
end of the lake over a bridge more than a mile long. So pure was the water
that as we looked down upon it, we plainly beheld the trout swiming
beneath.
Leaving the lake we passed through the pretty villages of Waterloo and
Seneca Falls. Here the dark green Seneca river rushes foaming over a bed
of rock, in a fall of forty seven feet. There are several mills and
manufactories upon its borders, and we observed several churches, an
academy, and many shops. Seneca! fair Seneca Lake, how can I describe
the gentle beauties of thy varied shores, and of that pretty town which so
adorns thy banks. This lake and its surrounding country, present a very
lovely scene. There is nothing grand about the lakelet; you must not
imagine it enclosed in the moutains of lakes George or Champlain; the style
is petite and delicate. Its Indian name was Jensequa, which has been
modernised into its present appellation. It is a placid, transparent sheet of
water, of very great depth, 4 miles by 35 long, and is said never to be frozen
over in the coldest winter. The road lay around the end of the lake, from
whence the eye wound over its fair pellucid waters to its cultivated shores,
adorned with handsome farm-houses, and country seats, and the massive
buldings of the college which occupies a commanding elevation near the
town—and the towers and steeples of the village peeping through the trees,
as if to catch a glimpse of the waters below. We stopped at a small stage
house in the lower and business end of the town, where we all descended
from the stage while the operation of changing horses and stages was going
on. A good sized parlor furnished with gay landscape paper received the
female part of the passengers, while the restless mankind part, repaired to
the shops, to inspect the manufactures of the town, or to refresh themselves
at the soda-water, and ice-cream shops. Once more seated in our stage
coach we ascended the hill, to the better portion of the town, where we
passed through the principal avenue of the place, upon each side of which
were arranged those pretty villas and gardens for which Geneva is so justly
celebrated. There were several churches in view, and a new presbyterian
half built. This, to us, was an interesting object, a token God was not
forgotten by the busy people below, or the wealthy ones around us.
Canandaigua with its lake and street of villas received our
commendations. There we dined at a very pretty and commodious Hotel,
having a fine view of the lake from its windows. Some of the lake trout
which appeared upon the table we found very fine. This lake is smaller than
those we have passed being 14 miles long. The main street is nearly two
miles long, and we drove through a mile of tasteful ‘garden-houses,’
surrounded by grounds laid out in a pleasing manner, adorned with flowers
and fine shade trees. The country from thence to Rochester is very
beautiful. Spotted with farms and villages, and woodlands covered with
groves of maple, hickory, bass-wood, elm, and evergreen trees. It was
nearly dark around us, when we were told the city was in view, and against
the bright evening sky we beheld in the distance the towers and spires of
Rochester. When we arrived we drove to the Rochester House. After some
refreshment we bade our companions adieu; promising to meet at an early
hour the next morning and drive over the town before we left it for
Lockport—and then were glad to rest, for we had come a long day’s
journey and in spite of good roads and commodious coaches, fine spirited
horses, and good drivers, we were very much fatigued.
Well do the inspired writers compare man and his brief existence to a
flower that early withereth—to a shadow—a cloud that quickly vanisheth—
one day here, and the next gone. Truly saith Job, ‘thine eyes are upon me
and and I am not,’ a just figure of man’s fleeting life. Never have I found
the truth of these comparisons more striking than at the present moment. I
told you of the amiable intellectual clergyman, who with his daughter
agreed to meet us early this morning—when that morning came he was in
eternity! At two o’clock last night we were aroused by a messenger from
Miss T. saying her father was very ill. We followed the servant through the
dark and lonely halls into the chamber where ‘the good man met his fate.’
Yes, all was over. Around the room in attitudes of mournful musing sat the
keeper of the Hotel, some servants, and several ladies who had arisen to do
all in their power to soothe the sufferer’s pains. All had been done that was
possible, but in vain. Upon the bed, lay a silent corpse, whose countenance
bespoke a death of agony—it was all that now remained of that good and
kind old man, that tender father, whose refined manners and intellectual
conversation, had charmed us so much the day before. But his high
intellect, his talents, his agreeable converse, of what avail were they all to
him now, had they not been joined to deep heart-felt piety, and been
devoted to the interests of religion. He had died far from his home, with no
friends near him except his daughter—his last hour passed away in a hotel
among strangers—yet spare your sympathy, for he died happy. The
everlasting arms were supporting him, a tender father was waiting to
receive him in those heavenly mansions where death and sorrow can never
come. He was going to no unknown region, he was to meet no stranger
face, for his mind and his heart had ever been familiar with that celestial
home, now to be his eternally—he knew a welcome awaited him from that
Savior and that God, with whose spirit he had ever held communion
through a long life spent in devotion and in acts of beneficence. It was the
wish of the celebrated Archbishop Leighton that he might die at an inn, thus
to be more forcibly reminded he was a pilgrim upon the earth—his wish
was fulfilled, for he died at the Bell Inn, London.
With what terms of praise high enough shall I speak of the people of
Rochester. When the news of this sad event spread, they surrounded the
bereaved daughter with sympathizing hearts, and offers of service. The
persons belonging to the house, and the boarders, with many physicians and
clergymen with ther families, were anxious to cheer the heart of the sad
survivor, and to lighten her mournful duties. The services of the Episcopal
church were read over the body by the Rev. Mr. W. a young English
clegyman of great talent and piety. The persons assembled near, seemed
much affected with this solemn event. May God bless this sudden
providence to them and to us. Uniting in a procession we accompanied the
corpse to the canal boat, where bidding adieu to Miss T. we left her to
pursue her dreary journey of five hundred miles, accompanied only with
hired attendants. With what comfort did we see in her the power of religion
elevating the soul above the trials and sorrows of life. Nothing else could
have supported this bereaved daughter through so heart-rending a
dispensation. But she knew in whom she believed. She saw from whom the
blow came, and her faith told her it was done in mercy. As we were to leave
Rochester the next morning, some of our kind friends called that afternoon
and insisted upon driving us through the town. It being our only chance of
seeing this celebrated city, we accepted their kindness, although the scenes
of the morning had unfitted us for anything but retirement.
As we drove along we were astonished at the extent and beauty of this
city. It was you know founded in 1812, and now contains 22,000
inhabitants. We had heard of its rapid rise, but supposed it must consist
mostly of wooden buildings as is often the case in new settlements, and our
surprise was the greater to find it built in the most solid manner. Churches,
houses, hotels and banks, court house and arcade, markets were all of
marble or stone. There are here fourteen churches[2] some of them quite
handsome. The Episcopal Church of St. Paul’s, is a fine gothic edifice of
grey stone—the church which enjoys the ministration of the Rev. Mr. W.
mentioned above, is also handsome, of gothic form, neatly edged with
brown free stone—the presbyterian is of grey plaster supported by
substantial abutments—the baptist, where Mr. C. officiates, one of our
active friends of the morning; a neat brick edifice—also catholic, methodist
and bethel for the canal men. The streets are many of them McAdamized.
There is a fine park here surrounded by neat railings where the children of
the neighborhood are brought to take exercise. But what most elicited our
admiration were the private dwellings, which in number and beauty are
seldom equalled in our cities. They are spacious, built of marble or stone, in
gothic or grecian form surrounded by wings and piazzas, and out-buildings
and grounds handsomely laid out, adorned with shade trees, shrubbery and
flowers. They are delightful retreats from the city’s dust and noise; make
fine playgrounds for the children, and altogether evince much taste and
wealth. How much better is it for men of fortune, to secure for themselves
and families, pure air and room for exercise, instead of squeezing, as they
do in our city, into houses only 30 by 100 feet, as is too much the custom in
our cities. The wealth lavished upon gay entertainments would procure
space where their children might gain health and strength. A frolic upon the
green sward is much more conducive to health, than a sober city walk
beside a nurse. I often see these palid pitiable little creatures in our streets
walking as gravely and demurely as some old octogenarian. A child without
gaiety is as cheerless as a landscape without sun.
The Genesee river divides the city into two parts, and is crossed by three
bridges and the two aqueducts of the Erie canal. The oldest of these is a
very fine piece of hewn stone work 804 feet long supported by eleven
raches. They were building another aqueduct, which is 858 feet long and 28
in height[3], and the music of the rushing river was almost drowned by the
mason’s hammer.
Beside this canal there is another called the Genesee valley canal from
Rochester to Olean, 119 miles. The Genesee falls are very pretty, consisting
of rapids through the city, and in the suburbs it plunges over a circular rock
into a deep dell. The whole fall through the city is 268 feet; 97 at the
cascade. There is another cataract farther down the river, which falls 106
feet. This is at Carthage, two miles below, and here is the port at which the
lake steamboats stop. A rail road runs to this place. There was not much
water in the river, and we did not see the falls in their greatest perfection,
but still there was great beauty in the feathery foam which fell in snowy
masses over the dark rock. These cliffs are old red stone and limestones—
with feruginous sand rock, and argillaceous iron ore; supposed by
geologists to be equivalent to the Caradoc series. Upon the summit of the
cliff opposite to us was a range of solid stone mills, from whence we obtain
that fine Genessee flour, ground from the wheat in the fertile region around.
Five hundred thousand barrels of flour are turned out in a year. There are
twenty-two of these mills. The little streams which trickle down the rocks,
are stolen from the river to turn the wheels. Our kind friends were anxious
to drive us to Mount Hope, a celebrated cemetery a few miles from the city,
but time was wanting for this and many other proposed pleasures. A distant
view of Lake Ontario is said to be obtained from this hill. We returned
home through some of the business streets, which, particularly Maine and
Buffalo, were filled with busy people, waggons of home or foreign produce,
while the long ranges of shops were gay with dry goods hanging from the
doors, and piled with every comfort and luxury. Stages were landing or
taking up passengers, canal boats were arriving and departing and every
thing we saw denoted a striving and thriving population.
L E T T E R V.
June 25th, 1840.
Dear E.—We left Rochester this morning at eight o’clock, in a fine stage
and four horses, for Lockport, 64 miles distant, for which we were to pay
two dollars and fifty cents each, dinner on the road, included. It was with
much regret that we parted from this interesting city, for, although we had
been there but a short time, we had seen enough to be able to appreciate its
beauties, and the sterling qualities of its beneficent and refined inhabitants.
We passed through several pretty villages, and observed with pleasure the
farm houses and even the meanest cabins were decorated with roses,
geraniums, honey-suckles and other flowers; a pleasing custom which I
wish was more followed among us. In one of the villages, I think its name
was Greece, I observed a neat grave yard enclosed in a handsome stone
fence and iron railing, where ‘the rude forefathers of the hamlet sleep,’
while around the tombs the kind hand of surviving friends had planted roses
and drooping willows. A great part of our way lay over the famous ridge
road, an elevation of ground about as wide as a common road formed of
sand and shells, and which is supposed once to have been the shore of Lake
Ontario, now about ten miles distant. The ground has very much this
appearance as the land between us and the lake is much lower, and level,
with marshy spots. It is in some places covered with a dense forest. There is
one thing however, which struck me as singular, the land declines the other
side of the road also, in some places leaving a narrow ridge to ride upon,
which is not the ordinary form of a lake shore. Why may it not have been a
public road, formed by that indefatigable race of diggers, the mound
builders, as a thoroughfare between two of their cities. It might still have
been the border of the lake, but swampy and marshy ground. If we are to
believe Mr. Delafield[4] these people were the descendants of the builders
of Babel, and when dispersed by the confusion of tongues wandered about
the world and at last found themselves in America. Here they have thrown
up pyramidial mounds in imitation of their ruined tower on the plains of
Shinar. The Arabs have a tradition that Nimrod, disappointed in his purpose
of reaching heaven by building a tower, constructed a chariot, to which he
placed a pair of wings, and thus hoped to enter the celestial regions. Alas!
since the days of Nimrod how many like him, have sought to attain the
courts above, by their own strenuous exertions.
Dear me, how I have wandered from the ridge road. The celebrated
traveller, McKenney, believes this to have been the border of the lake,
which broke away and ran over the State of New York, thus scooping out
the earth at the other side of the ridge. The lakes Geneva, Canandaigua,
Cayuga, etc., he believes to have been left by this flood. This agrees with
Dr. Mitchell’s theory of a vast lake having been once in this part of the
state, which burst through its southern shore at the Little Falls of the
Mohawk, and through the Highlands, flooding the coasts of New York with
alluvion. De Witt Clinton also, in his Canal report, remarks: ‘The general
position of the Little Falls, indicate the former existence of a great lake
above connected with the Oneida lake; as the waters forced a passage here
and receded, the flats were formed above, composed of several acres of
alluvion.’ In this alluvion trees are often found twelve feet under ground.
Darby observed marks upon the rocks at Little Falls fifty feet above the
river, showing the water had once stood so high.
At a distance we saw Brockport upon the canal, and soon after, at
Gainesville, we dined. We reached Lockport at five o’clock in the afternoon
and were shown into a neat comfortable hotel where we awaited the time of
starting in the cars. Lockport is a town of the mushroom order, having
arisen around the locks of the canal within a few years. The churches,
houses, and hotels, looked very respectable, and the rail-roads and canals
gave it quite a stirring appearance. The locks at the canal here are a great
curiosity. There are five double combined locks which carry the canal over
the ridge. There is also a deep cutting through the solid rock for some miles
which is very interesting. Many specimens of minerals have been
discovered here, as carbonate of lime, selenite, dogtooth spar, petrifactions,
etc. I promised to give you an account of all our expenses, so I will mention
now, we are to pay ninety-four cents each to Niagara, twenty miles, as I
shall not think of such mundane affairs while there. Our expenses at the
hotels have been two dollars a day each, and meals fifty cents each at all
our stopping places. Seated in the rail car we were soon on our road, and
fast dashing through a tolerably cultivated country, with several neat
mansions peeping through the trees. I trembled lest the land should remain
thus until we arrived at Niagara, for I could not bear to approach it through
petty villages and farms, but we soon left all cultivation behind and found
ourselves in a deep forest. While gliding rapidly along, the engineer’s bell
rang to scare some cow or other animal, as we thought, from the rail track.
Several of the passengers looked out, one pronouncing it a man, another a
cow, until, as we approached, we discovered it was an Indian female. She
was enveloped in a dark mantle from beneath which could be seen her
scarlet leggins richly embroidered with beads. With a slow and stately step
she paced the rail-track, the engineer’s bell and shrill whistle unheeded.
That she heard them was evident, for another Indian woman, her
companion, who walked outside the rail, stretched forth her hand as if in
earnest appeal, but the haughty young princess scorned to fly before her
country’s foe. The engine with slackened speed came near her and stopped;
then, and not until it had quite stopped, she condescended to walk off the
rail-way. As we passed I saw she was young and pretty, and her dark eye
flashed with a triumphant expression which said, ‘You dared not drive over
me! I scorned to be forced from the road by your bell, like an animal!’
‘Look out for the Falls! Prepare for Niagara!’ is the cry of all in the
coach. My heart began to beat—does not yours? Do be a little romantic, and
feel some emotion, while about to behold one of Nature’s greatest wonders.
I looked out; we were on the river’s bank, a high precipice of about two
hundred feet Far below rushed the river, of a green copper hue, or verdigris;
far up through the defile I caught a view of a mountain of mist, but I
resolutely turned away, for such snatches of views I have been told to avoid,
as bringing disappointment with them. The road swerved from the river, and
in a few minutes we found ourselves in the midst of the little village of
Niagara. When the train stopped we were surrounded by a host of porters,
struggling to secure us for their several favorite hotels. We chose the
Cataract house, from a friend’s recommendation, and from its appropriate
name. We had no cause to repent our decision as its accommodation and
attendance were every thing we could wish. We were shown into a neat
chamber, which to my delight looked out upon the rushing rapids. The tea
bell rang as we entered, and much to the annoyance of my impatient spirit,
my companion made it plain to me I should refresh myself before visiting
the Falls. Tea over, I had leave to go, and we were soon upon the pathway.
Shall I take you at once into the presence chamber of the divinity, or shall I
describe the halls and corridors as I pass through them to her throne? I think
a minute description will best please you. Niagara river, just before it
reaches the fall is divided into two parts; one rushing past the Canada shore,
plunges over the rocks making the crescent, or horse-shoe fall—this fall is
about one hundred and sixty feet high. The other half of the river passes
around an island, called Goat, or Iris island, and falls from the American
side. This island has been sacred from the foot of man until a few years
since, when a bridge was thrown across the rapids with much dexterity and
daring. Upon this bridge we will walk if you please, stopping one moment
to view the rapids. These constitute a very beautiful feature of the scene,
and, were it not for the falls, would be well worth a visit on their own
account. The river is a mile wide, and comes rushing and foaming over
rocks some ten or twelve feet high, looking, sea-faring men tell us, very
much like breakers, or a sea in a storm—the green waves heightening the
illusion. One is glad to be safely over this tumultuous water, especially as
the former bridge has been carried away. From the bridge you land upon
Bath island, containing about two acres of land, upon which is erected a
toll-house, and shop for the sale of Indian curiosities and canes. There are
also bathing houses here. A short bridge brings us to Goat Island, one-half a
mile long and a quarter wide. It is also called Iris, and as such I shall
designate it. The increased roar, the mist rising above the trees, urge you on,
and you pass the ‘curiosity shop’ and refreshments here offered, and hasten
on through many a winding forest path, until you gain the opposite side of
the island, where you find yourself upon the brink of a deep gulf into which
an ocean broken loose from its bounds is precipitated with astounding noise
and violence!.... This is the crescent fall on the Canadian shore. But linger
not here. Descend the island to the brink of the river, and cross the rapids
over a tottering, frail bridge, to the tower, which stands upon the precipice
at the edge of the falls. Ascend to the top, and lean over the railing, look
calmly down if you can, into the fathomless abyss of ocean, where the
waves are dashing; the foam whirling, and the winds rushing, amid the roar
of a thousand thunders eternally ascending. Deafened, confounded,
bewildered, you retreat in haste, fearful every moment the breakers which
are dashing against the tower, will tear it away from its foundation, and
plunge you into the fearful ocean depths below. At this place, and upon
table rock opposite, you see Niagara in all its power and terror. But if you
would behold it in all its ravishing beauty, you must go as we did, the next
morning before sunrise, and view it from the ferry house. To reach this spot,
you do not cross to Iris island, but follow the river bank to the American
fall, near which is the ferryman’s cottage, and at a little distance the ladder
which leads you down to the boat. Seated upon a rock, in front of the
cottage, we feasted our eyes with unearthly beauty. Beside you is the
American fall, tinged with a delicate apple or beryl green hue. One delights
to follow with the eye this fair translucent arch, as it plunges far down into
the water nearly two hundred feet below us. You have but a sideling view of
this fall here. Looking past it you see the dark foliage of Iris island, and
beyond, the Canadian fall. This immense mass of water falls over rocks in
the form of a crescent, and is tinted with an elysian loveliness which you
have never beheld, and never can conceive, let me write pages upon it.
Earth has never produced water of the like hue: something of the emerald,
but more rich, more vivid. This green, spotted, and embroidered as it is,
with wreaths of snow white foam, presents the most charming and unique
effect imaginable. In some places the water pitches over perfectly smooth,
as if an emerald arch; and so pellucid, that you may distinctly see through it
the white foam that is churned from the rocks over which it flows. As we
reached the spot from whence this is seen, the sun arose above the trees,
and immediately two glorious rainbows spanned the river from shore to
shore! and the mist which was rising high in the air, took the tint of the rose,
which faded, only to be replaced by the most gorgeous prismatic hues.
Never had imagination pictured any thing so glorious as that scene: a
tremendous fall of green and white water; a gay colored rainbow; rosy mist;
azure sky, and shores of various shades. It was a creation which belonged
not to earth. It seemed as if the celestial city was before us, with its gates
and walls of sapphire, of emerald, of ruby, and of gold. The waters of life
that flow through the city of God, seemed rushing past us, for the scene was
altogether unearthly, and our feelings were elevated to that sublime
architect, who could create such surpassing beauty. Earth and its cares,
home and its joys are all forgotten, and we feel as if we could ever recline
before the throne of that mysterious presence, and watch untiring those
clouds of incense which are rising before it forever. When we left the scene,
we trod in solemn silence, as if on holy ground. The violence with which
the water pours over the rocks has worn them away, and the river has
broken its way up from Lake Ontario at the rate of a rood in three years. It
is supposed, when first discovered, to have been near the Clifton House on
the Canadian shore, and the ferry house at the American.
June 26th.—This morning we descended the cliffs by a staircase and
crossed to the Canadian shore. The boat was tossed about like a shell upon
the whirling waves, and as they looked up at the mass of water tumbling so
near them, and at the boiling water two hundred and fifty feet deep, under
us, some of our fellow passengers became a little nervous. My whole soul
was so absorbed in contemplating the wondrous scene, that I felt no terror.
A sentinel in the scotch costume greeted our eyes when we landed telling us
we were now in a strange land among another people. A winding walk up
the cliff, leads you to Clifton House, a celebrated Canadian hotel. From the
balconies of this house, is one of the most imposing views of the Niagara
falls. You see the whole at once, while from the American side you see only
a part at a time. Still, if not so grand, the view is more varied and more
beautiful upon the opposite shore and from Iris Island. Every one says it is
ridiculous to attempt to describe these falls, but, I have promised to give
you daguerreotype views, and will endeavor to sketch the outlines—the
shading, and the impressions of the scene can only be given by the place
itself. Imagine a crescent of water a mile long, plunging with awful
violence as if the foundations of the great deep had broken up again, from a
cliff nearly 200 feet high. According to McKenney 15,000,000 tons of
water are poured over the rocks in 24 hours. A green island divides this fall
into two unequal parts. Table rock, upon the Canadian shore is at the edge
of the falls, and projects over the cliff where you may stand with nothing
between you and the boiling ocean below. So close is it to the water that the
waves wash over part of it, and it is almost always covered with mist and
spray. If it be glory to be buried in Niagara, you may here hope for that fate,
as a portion of the rock has already fallen, and a large crack shows you the
remainder will soon follow. From this spot, is said to be the finest view, as
the eye embraces the whole circle of waters; but, as it was one of the days
when the mist takes that direction, I saw but little of this. I found myself
upon a slippery rock, a shelf between heaven and earth, with waves of spray
breaking over me, and a furious mist dashing into my face—a noise of
waters was in my ears, a white foam rushed wildly past, and I felt as if
caught up in the sky in a whirlwind and driving snow storm. We waded
back through the wet grass and ran into the Pavilion to avoid the spray
dripping from the eaves. This house besides being a curiosity shop is the
residence of the guide who will conduct you down a long staircase, and
behind the fall if you wish—as I had no penchant for being drenched, half
drowned and suffocated I did not attempt this exploit. We descended this
morning the American side and ventured a little behind that fall. One feels
very much as an Israelite making his exode, with a wall of water at his side
‘where the flood stood upright.’
When once in, you see a glorious chamber with dome and walls of
emerald rendered transparent by the morning sun. You might imagine
yourself in one of those crystal caves where the sea nymphs congregate,
beneath the arches of the sea. On the road from table rock to Clifton House,
there is another building where there is a fine museum containing 4,000
specimens of Indian curiosities, animals, minerals &c., many of them from
that region. The trees about here are most of them evergreen. The regular
yellow pine grows here and the silver fir with its white lined leaves and
purple cones and the fan leaved larch growing 100 feet high. The rocks of
Niagara are secondary limestone and sandstone, abounding with veins and
nodules of various minerals—among them selenite, calcareous spar—
petrifactions—tufa from the cave, and many others. I believe I have
sketched for you every thing regarding these falls—gigantesque phenomene
as La Vaseur calls them. Still I do not expect to give you any idea of them,
for no one who ever wrote, conveyed an impression of the reality to me. I
might make a pyramid of expletives, and when all the superbs beautiful’s,
majestic’s and touching’s are expended, you will say when you come, ‘the
half has never been told me!’ Many have been disappointed here chiefly
because the scenery around the falls is not as imposing as they had
imagined. Some would have a range of lofty mountains as a back scene; or
a crest of naked rocks towering above the falls; but I fancy these are of the
class of contradictionists who make a respectable figure in conversation
merely by opposing every thing. They thus obtain a hearing, are able to
enter into an argument, when no other means would gain them a listener. He
who formed this imposing scene is a better judge of the sublime and
beautiful. A range of mountains would materially injure the effect, as it
would by contrast take away from the height of the water. The cataract
would be a secondary object, but seated as it is in a level region of country,
it is the first object that strikes the eye—- a gem on natures forehead. There
are many drives in this neighborhood to various interesting places, such as
springs, whirlpools, battlefields &c. The parade ground is also a favorite
place of resort. A regiment of 700 soldiers are reviewed upon the Canadian
shore. We hired a carriage at the Clifton House and after a short drive found
ourselves upon a beautiful plain above the falls, surrounded by guard
houses, and barracks. The plain was soon filled with soldiers, who came
marching up in separate detachments from every direction. They were tall
fine formed men, all of one height dressed in the Scotch costume,
consisting of the short plaid skirt, stockings laced with red, cap and a cloud
of black plumes. They were well drilled, and marched, counter-marched
and went through all their evolutions as one man. The dress is picturesque,
but must be a cold one in these regions. A pantaloon over the naked knee, I
think would be an improvement. I could see soldiers, although not as well
drilled, at home, so I was glad to turn my course towards that rolling flood
below. From this plain is a fine view of the rapids above the cataract, and of
Iris Island, which seems to have floated to the brink of the precipice, like
one of the Mexican floating islands. We spent the afternoon upon Iris
island. In the little curiosity shop we refreshed ourselves with delicate white
strawberries grown upon the island, covered with rich cream. Here also we
added to our stock of Indian bags and moccasins. Among the articles in the
shops at the village I admired most a large living eagle which was chained
to his perch. His feathers were black and white, and his beak and claws
yellow, with a ruff of grey about his neck. I pitied the poor captive as he
stood gazing sadly out apparently listening to the roar of the falls, and
longing to be at large in his native forest once more.
The village of Tuscarora Indians is sometimes visited, much against their
wishes however. The Indian nations have never lost the remembrance of
their former power, and their present degradation. They look upon us as
usurpers, who have wrested from them the land of their fathers, and have
never forgiven us. They count themselves our prisoners, and are indignant
that we should come and gaze upon them in their fallen state as objects of
curiosity. Their village is built upon the high shore of Niagara about eight
miles below the falls, commanding a fine prospect of the river and lake.
They are under the care of a missionary who has been the means of
converting fifty out of the three hundred. This tribe once belonged to the
confederacy of five nations, but came originally from North Carolina, and
are living upon the proceeds of the sale of their land there and their trade.
Some of them are prosperous, industrious farmers, while the women
embroider beautifully, with beads and stained porcupine quills, upon birch
bark and deer skin. These they dispose of at the shops, and to strangers at
the Hotels. Upon these occasions, I am struck with the difference between
this proud race and our own. A pedler or travelling shopman comes in,
unpacks his wares, holds up every article, insists upon its worth and beauty,
and urges you to buy—with the Indian it is otherwise. At our hotel, while
ascending after dinner to the dining room, one is struck by the sight of a
row of dark beings sitting upright upon the settees in the halls envelloped in
cloaks of scarlet or black, richly embroidered with beads or adorned by
pieces of tin cut in flowers and tacked on. Their eyes are fixed upon the
ground, their long hair falls over their faces, and an expression of profound
melancholy sits upon every countenance. You stand before them and gaze
upon them, but silent, grave, and motionless they sit, like the band of
conscript fathers awaiting the approach of Attila. You at last ask, ‘Have you
any moccasins!’ with a dignified motion they throw open their cloaks, and
their laps are filled with articles for sale. You ask the price—a low musical
voice tells you the amount in a very foreign accent, and that is all I could
ever obtain from an Indian woman although I made many efforts while at
Niagara, and they can both speak and understand English.
I never saw but one of them smile. I asked her what she had for sale in
her lap—she threw it open, and behold a pretty Indian cupid asleep in a
birch cradle, swathed and bandaged in their peculiar fashion. Titania would
have quarrelled for it. At my start of surprise and admiration, a moonbeam
smile flashed over her face and then all was dark and gloomy as before. The
celebrated Timothy Flint tells us, ‘the Indians are a melancholy musing
race; whatever emotion or excitement they feel, goes on in the inner man.’
So close an observer as he was, and living so long among them, his views
can be relied on as being correct. The Indians have always been noted for
their strong attachment to their children, and a stranger among them has
only to praise the papoose to win his way to the parents heart.
June 27th.—I could not have believed parting with Niagara would have
caused such sorrow. The lofty, and celestial emotions which are produced
when in the presence of this one of God’s most beautiful creations you are
unwilling to lose. You feel ‘it is good to be here’—and you dread to leave
this holy ground to enter again into scenes which will do much to efface
these pure emotions. A glimpse of heaven has been vouchsafed you, and
most reluctantly you return to earth again. Slowly we sat out this morning
to take a last farewell. We had seen it in all its brightness and we now

Concepts and Experimental Protocols of Modelling and Informatics in Drug Design Om Silakari Full Chapter

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Concepts and Experimental Protocols of Modelling and Informatics in Drug Design Om Silakari Full Chapter

Uploaded by

Copyright:

Available Formats

Concepts and Experimental Protocols

of Modelling and Informatics in Drug

Pankaj Kumar Singh

British Library Cataloguing-in-Publication Data

For Information on all Academic Press publications

Publisher: Stacy Masucci

Chapter 1: Fundamentals of molecular modeling ...................................................... 1

Chapter 2: QSAR: Descriptor calculations, model generation,

2.2 Fundamental principle of QSAR ..................................................................... 31

Chapter 3: Small molecule databases: A collection of promising

Chapter 4: Database exploration: Selection and analysis of

Chapter 5: Homology modeling: Developing 3D structures of target

Chapter 6: Molecular docking analysis: Basic technique to predict

Chapter 7: Molecular dynamic simulations: Technique to analyze real-time

Chapter 8: Water mapping: Analysis of binding site spaces

8.6 Conclusion........................................................................................................ 193

Chapter 9: Ligand-based pharmacophore modeling: A technique utilized for

Chapter 10: Fragment based drug design: Connecting small substructures

10.3.4 Multitasking computational model approach....................................... 244

Chapter 11: Scaffold hopping: An approach to improve the existing

Chapter 12: Hotspot and binding site prediction: Strategy to target

Chapter 13: In-silico SNP analysis: An aid to identify novel potential

13.4.1 SIFT ................................................................................................... 287

Chapter 14: ADMET tools: Prediction and assessment of chemical ADMET

Chapter 15: Cheminformatic tools: Identify suitable synthesis procedures

Chapter 16: Statistical methods and parameters: Tools to generate and

Fundamentals of molecular modeling

1.1 Molecular modeling

1.2 Molecular representation

Concepts and Experimental Protocols of Modelling and Informatics in Drug Design.

1.2.1 Cartesian coordinate

1.2.2 Polar coordinate

1.2.3 Internal coordinate

1.3 Computer graphics

1.4 Molecular models

1.4.1 CPK models

1.4.2 Dreiding models

1.4.3 Computer models

Computer models can be used to draw a virtually limitless variety of molecular

1.5 Molecular surfaces

1.5.1 Van der Waals surface (VWS)

1.5.2 Solvent accessible surface

1.5.3 Solvent excluded surface

1.5.4 Charged partial surface area (CPSA)

1.6.1 GPU hardware

1.7 Principles of molecular modeling

1.7.1 Molecular mechanics

1.7.1.1 Energy minimization

1.7.1.2 Classes of force field methods

1.7.1.3 List of some important common force fields

Sunday, June 22d.—This morning we visited the first presbyterian

You might also like