Principles of Molecular Recognition

212 Pages·1993·3.105 MB·English

by  A. D. Buckingham (auth.), Professor A. D. Buckingham, Professor A. C. Legon, Professor S. M. Roberts (eds.)

Principles of Molecular Recognition
Principles of
Molecular Recognition
Edited by
A.D. BUCKINGHAM
Department of Chemistry
Vniversity of Cambridge
A.C. LEGON and S.M. ROBERTS
Department of Chemistry
University of Exeter
Springer-Science+Business Media B.V.
First edition 1993
© 1993 Springer Science+Business Media Dordrecht
Originally published by Chapman & Hall in 1993
Softcover reprint of the hardcover 1s t edition 1993
Typeset in 1O/12pt Times by Thomson Press (India) Ltd, New Delhi
ISBN 978-94-010-4959-7
Apart from any fair dealing for the purposes of research or private study, or
criticism or review, as permitted under the UK Copyright Designs and Patents
Act, 1988, this publication may not be reproduced, stored, or transmitted, in any
form or by any means, without the prior permission in writing of the publishers,
or in the case of reprographic reproduction only in accordance with the terms of
the licences issued by the Copyright Licensing Agency in the UK, or in
accordance with the terms of licences issued by the appropriate Reproduction
Rights Organization outside the UK. Enquiries concerning reproduction out
side the terms stated here should be sent to the publishers at the Glasgow
address printed on this page.
The publisher makes no representation, express or implied, with regard to the
accuracy ofthe information contained in this book and cannot accept any legal
responsibility or liability for any errors or omissions that may be made.
A catalogue record for this is available from the British Library
Library of Congress Cataloging-in-Publication data
Principles of molecular recognition / edited by A.D. Buckingham, A.C.
Legon, and S.M. Roberts. --Ist ed.
p. cm.
Includes bibliographical references and index.
ISBN 978-94-010-4959-7 ISBN 978-94-011-2168-2 (eBook)
DOI 10.1007/978-94-011-2168-2
1. Molecular recognition. 1. Buckingham, A.D. (Amyand David)
II. Legon, A.C. III. Roberts, S.M. (Stanley M.)
QP517.M67P75 1993
547.7'044242--dc20 93-1459
CIP
Printed on acid-free text paper, manufactured in accordance with ANSI/NISO
Z39.48-1992 (Permanence of Paper).
Preface
The importance of molecular recognition in chemistry and biology is reflected
in a recent upsurge in relevant research, promoted in particular by high-profile
initiatives in this area in Europe, the USA and Japan. Although molecular
recognition is necessarily microscopic in origin, its consequences are de facto
macroscopic. Accordingly, a text that starts with intermolecular interactions
between simple molecules and builds to a discussion of molecular recognition
involving larger scale systems is timely. This book was planned with such a
development in mind.
The book begins with an elementary but rigorous account of the various
types of forces between molecules. Chapter 2 is concerned with the hydrogen
bond between pairs of simple molecules in the gas phase, with particular
reference to the preferred relative orientation of the pair and the ease with
which this can be distorted. This microscopic view continues in chapter 3
wherein the nature of interactions between solute molecules and solvents or
between two or more solutes is examined from the experimental standpoint,
with various types of spectroscopy providing the probe of the nature of the
interactions.
Molecular recognition is central to the catalysis of chemical reactions,
especially when bonds are to be broken and formed under the severe con
straint that a specific configuration is to result, as in the production of enan
tiotopically pure compounds. This important topic is considered in chapter 4.
The origin of the catalytic power of enzymes is examined in chapter 5 where
methods of simulating details of the interaction between an enzyme and its
substrate are described, with special reference to the catalytic reaction of
staphylococcal nuclease. It is then a natural step to address the question of
drug discovery in the context of molecular recognition (chapter 6). Finally, the
role ofthe dynamical motion of proteins in determining their functionality and
properties is illustrated in chapter 7 through the example of met myoglobin in
water using the technique of computer simulation.
The editors are grateful to the distinguished scientists who have contributed
to this book and hope that their efforts will be helpful to students and to those
beginning research in this exciting and challenging field.
A.D.B.
A.c.L.
S.M.R.
Contributors
Dr J. Aqvist Department of Molecular Biology,
Uppsala Biomedical Centre, Box 590,
S-75124 Uppsala, Sweden
Dr J.M. Brown Dyson Perrins Laboratory, University of
Oxford, South Parks Road, Oxford
OX13QY, UK
Professor A.D. Buckingham Department of Chemistry, University of
Cambridge, Lensfield Road, Cambridge
CB21EW, UK
Dr L.A. Findsen Department of Medicinal and
Pharmaceutical Chemistry, University of
Toledo, Toledo, OH 43606, USA
Dr P.J. Guiry Dyson Perrins Laboratory, University of
Oxford, South Parks Road, Oxford
OXI3QY, UK
Professor A.C. Legon Department of Chemistry, University of
Exeter, Stocker Road, Exeter EX4 4QD,
UK
Dr V. Lounnas Department of Chemistry, University of
Houston, Houston, Texas 77204-5641,
USA
Professor D.J. Millen Department of Chemistry, University
College London, 20 Gordon Street,
London WCIH OAJ, UK
Professor B.M. Pettitt Department of Chemistry, University of
Houston, Houston, Texas 77204-5641,
USA
Professor S.M. Roberts Department of Chemistry, University of
Exeter, Stocker Road, Exeter EX4 4QD,
UK
Dr J. Saunders Glaxo Group Research Limited, Greenford
Road, Greenford, Middlesex UB6 OHE,
UK
viii CONTRIBUTORS
Dr S. Subramanian Department of Biophysics, University of
Illinois, Urbana, IL 61801, USA
Professor M.C.R. Symons Department of Chemistry, The University,
Leicester LEI 7RH, UK
Professor A. Warshel Department of Chemistry, University of
Southern California, Los Angeles,
California, 90089-1062, USA
Dr A. Wienand Dyson Perrins Laboratory, University of
Oxford, South Parks Road, Oxford
OX13QY, UK
Contents
Preface v
Contributors VII
1 Intermolecular forces 1
A.D. BUCKINGHAM
1.1 Introduction 1
1.2 The Born-Oppenheimer approximation 2
1.3 Molecules and forces 3
1.4 The hydrophobic effect 4
1.5 Classification of intermolecular forces 6
1.5.1 Electrostatic energy 6
1.5.2 Induction energy 7
1.5.3 Dispersion energy 8
1.5.4 Resonance energy 8
1.5.5 Magnetic interactions 9
1.5.6 Short-range interactions 9
1.6 Vibrational contributions to intermolecular forces 10
1. 7 Magnitudes of contributions to the interaction energy 11
1.8 Forces between macroscopic bodies 12
1.9 The effect of a medium 12
1.10 The hydrogen bond 14
References 15
2 Molecular recognition involving small gas-phase molecules 17
A.C. LEGaN and D.1. MILLEN
2.1 Introduction 17
2.2 How to determine the angular geometry and strength of intermolecular binding
for an isolated dimer 18
2.3 Empirical observations about angular geometries in the series B ... HX 22
2.4 An electrostatic model for the hydrogen bond interaction: the Buckingham-
Fowler model 25
2.5 The electrostatic model and non-bonding electron pairs 26
2.6 A point-charge representation of non-bonding electron pairs 31
2.7 Isomerism in weakly bound dimers: incipient molecular recognition 36
2.8 Dimers with two interaction sites 39
2.9 Consequences of the rules for angular geometries in the solid state 41
References 41
3 Spectroscopic studies of solvents and solvation 43
M.C.R. SYMONS
3.1 Introduction 43
3.1.1 History 43
X CONTENTS
3.2 Background 44
3.2.1 Hydrogen bonding 44
3.2.2 Hydrophobic bonding 46
3.2.3 Comments on some common solvent systems 47
3.3 Ultraviolet spectroscopy 48
3.3.1 Neutral solutes 48
3.3.2 Ions 49
3.4 ESR spectroscopy 51
3.4.1 ESR studies of ion pairing 51
3.4.2 Solvation of aromatic nitro-anions 54
3.4.3 Solvation of neutral nitroxides 55
3.4.4 Gain and loss of solvation 56
3.5 Nuclear magnetic resonance studies 57
3.5.1 Solute shifts 57
3.5.2 Use of 1 H NMR shifts to study solvation of ions 59
3.5.3 Relaxation studies 59
3.6 Vibrational chromophoric probes 60
3.6.1 Triethylphosphine oxide 61
3.6.2 Cyanomethane 64
3.6.3 Acetone 65
3.7 Near infrared studies 66
3.7.1 Free OH groups 66
3.7.2 Some consequences of the 'free-group' postulate 68
3.7.3 Use of overtone infrared (NIR) to study solvation of ions 71
3.8 Use of results from vibrational spectroscopy to interpret magnetic
resonance data 72
3.8.1 NMR shifts 73
3.8.2 ESR data 75
3.8.3 Why are solvation numbers for solutes greater in water than in
other protic solvents? 75
3.9 Solvation in biological systems 75
3.9.1 Solvation changes 76
3.9.2 NMR spectroscopy 76
3.9.3 Solvation of small biomolecules 76
References 76
4 Origins of enantioselectivity in catalytic asymmetric synthesis 79
1.M. BROWN, P.l. GUIRY and A. WIENAND
4.1 Introduction 79
4.2 Homogeneous hydrogenation with rhodium complexes 80
4.2.1 Catalytic kinetic resolution and directed hydrogenation 84
4.3 Hydrogenation with ruthenium complexes 87
4.4 Carbon-carbon bond formation through cross-coupling 96
4.5 Carbon-carbon bond formation through allylic alkylation 103
References 106
5 Molecular recognition in the catalytic action of metallo-enzymes 108
1. AQVIST and A. W ARSHEL
5.1 Introduction 108
5.2 Methods for simulating reactions in enzymes and solution 110
5.2.1 Molecular orbital approach 110
5.2.2 The EVB model 112
5.3 Application to the staphylococcal nuclease reaction 116
5.3.1 Free energy profile for the SNase reaction 118
5.3.2 Effects of metal ion substitutions 123
CONTENTS xi
5.4 Concluding remarks 134
Acknowledgements 135
References 135
6 Drug discovery 137
1. SAUNDERS
6.1 Introduction 137
6.2 Receptors as targets for drug design 139
6.2.1 Alzheimer's disease and the muscarinic receptor 141
6.2.2 Angiotensin-II antagonists in hypertension 145
6.3 Enzymes as targets for drug design 151
6.3.1 HIV protease inhibitors as anti-AIDS drugs 152
6.3.2 Emphysema and elastase 159
6.4 Drug discovery by screening: concluding remarks 164
Acknowledgements 165
References 165
7 Time scales and fluctuations of protein dynamics: metmyoglobin
in aqueous solution 168
L.A. FINDS EN, S. SUBRAMANIAN, V. LOUNNAS and
B.M. PETTITT
7.1 Introduction 168
7.2 Methods 170
7.3 Spatial and temporal fluctuations 171
7.3.1 The approach to equilibrium 171
7.3.2 Structure and dynamics 180
7.4 Conclusions 191
Acknowledgements 192
References 192
Index 195
1 Intermolecular forces
A.D. BUCKINGHAM
1.1 Introduction
The fundamental basis for molecular recognition is provided by the potential
energy surface that represents the interaction energy of two or more molecules
in a cluster as a function of their mutual separation and orientation.
Molecules attract one another when they are far apart, since liquids and
solids exist. They repel one another when close, since the densities ofliquids and
solids have the values they do under normal conditions of temperature and
pressure. Figure 1.1 illustrates this important truth and shows a typical inter
action energy u(R) of two spherical molecules as a function oftheir separation
R. For two argon atoms, the well-depth e is 0.198 x 10-20 J (elk = 143 K) and
the equilibrium separation Re is 3.76 X 10-10 m [ll
The number of independent variables upon which the intermolecular energy
depends increases as the molecular size increases. For two atoms there is only
one variable R (Figure 1.1), and for an atom interacting with a diatomic there
a, a
are the three variables R, r where is the angle between the internuclear axis
of the diatomic and the line joining the atom to the centre of mass of the di
atomic, and r is the separation ofthe nuclei in the diatomic. For two diatomics
a a
there are six (R, 1, 2, c/J, r l' r 2)' where c/J is the angle between the planes contain
ing the line of centres and the internuclear axis of each molecule. In the general
case, for molecules containing N 1 and N 2 nuclei, there are 3(N 1 + N 2) - 6
independent variables of which 3N 1 - 6 and 3N 2 - 6 are vibrational coordi
nates in each molecule and the remaining six (R,a1,X1,a2,X2'c/J) (Figure 1.2)
determine the relative positions and orientations of the molecules; X1 and X2
a a
give the orientation of molecules 1 and 2 about their axes at angles and to
1 2
the line of centres. The intermolecular potential surface of the water dimer
(H 0h has twelve variables, six of which are related to the vibrational coordi
2
nates of the two H 0 molecules.
2
The six relative translational and orientational degrees of freedom of an
interacting pair of non-linear polyatomic molecules generally fluctuate slowly
compared to the intramolecular vibrations. For some purposes, such as
rotational relaxation, it may be sufficient to average u over the vibrational
motion, thereby reducing the number of variables upon which u depends to
just six. For vibrational relaxation of a particular mode, it may sometimes be