Computational and theoretical tools for understanding biological processes at the molecular level is an exciting and innovative area of science. Using these methods to study the structure, dynamics and reactivity of biomacromolecules in solution, computational chemistry is becoming an essential tool, complementing the more traditional methods for structure and reactivity determination. Modelling Molecular Structure and Reactivity in Biological Systems covers three main areas in computational chemistry; structure (conformational and electronic), reactivity and design. Initial sections focus on the link between computational and spectroscopic methods in the investigation of electronic structure. The use of Free Energy calculations for the elucidation of reaction mechanisms in enzymatic systems is also discussed. Subsequent sections focus on drug design and the use of database methods to determine ADME (absorption, distribution, metabolism, excretion) properties. This book provides a complete reference on state of the art computational chemistry practised on biological systems. It is ideal for researchers in the field of computational chemistry interested in its application to biological systems.
Modelling Molecular Structure and Reactivity in Biological Systems
By Kevin J Naidoo, John Brady, Martin J Field, Jiali Gao, Michael HannThe Royal Society of Chemistry
Copyright © 2006 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-668-3Contents
Molecular Conformation and Electronic Structure of Biomolecules,
ELECTOWEAK QUANTUM CHEMISTRY AND THE DYNAMICS OF PARITY VIOLATION IN CHIRAL MOLECULES Martin Quack, 3,
CHARACTERIZATION OF PROTEIN FOLDING/UNFOLDING AT ATOMIC RESOLUTION R. Day and V. Daggett, 39,
THE ROLE OF ATTRACTIVE FORCES ON THE DEWETTING OF LARGE HYDROPHOTIC SOLUTES Niharendu Choudbury and B. Montgomery Pettit, 49,
STRUCTURE AND MECHANISM OF THE ATPASE VCP/P97: COMPUTATIONAL CHALLENGES FOR STRUCTURE DETERMINATION AT LOW RESOLUTION A.T. Brunger and B. DeLaBarre, 58,
THEORETICAL ANALYSIS OF MECHANOCHEMICAL COUPLING IN THE BIOMOLECULAR MOTOR MYOSIN Q. Cui, 66,
MOLECULAR DYNAMICS AND NEUTRON DIFFRACTION STUDIES OF THE STRUCTURING OF WATER BY CARBOHYDRATES AND OTHER SOLUTES J.W. Brady, P.E. Mason, G.W. Neilson, J.E. Enderby, M.-L. Saboungi, K. Ueda, and K.J. Naidoo, 76,
Chemical Reactivity in Biological Surroundings,
FROM PRION PROTEIN TO ANTICANCER DRUGS: QM/MM CARPARRINELLO SIMULATIONS OF BIOLOGICAL SYSTEMS WITH TRANSITION METAL IONS M.C. Colombo, C. Gossens, I. Tavernelli and U. Rothlisberger, 85,
SIMULATIONS OF ENZYME REACTION MECHANISMS IN ACTIVE SITES: ACCOUNTING FOR AN ENVIRONMENT WHICH IS MUCH MORE THAN A SOLVENT PERTURBATION Jill E. Gready, Ivan Rostov and Peter L. Cummins, 101,
THEORETICAL STUDIES OF PHOTODYNAMIC DRUGS AND PHOTOTOXIC REACTIONS Rita C. Guedes, Xiao Yi Li, Daniel dos Santos and Leif A. Eriksson, 119,
ACID/BASE PROPERTIES OF RADICALS INVOLVED IN ENZYME-MEDIATED 1,2-MIGRATION REACTIONS K. Nakata and H. Zipse, 132,
DEVELOPMENT OF A HETEROGENEOUS DIELECTRIC GENERALIZED BORN MODEL FOR THE IMPLICIT MODELING OF MEMBRANE ENVIRONMENTS M. Feig and S. Tanizaki, 141,
ASSESSMENT AND TUNING OF A POISSON BOLTZMANN PROGRAM THAT UTILIZES THE SPECIALIZED COMPUTER CHIP MD-GRAPE-2 AND ANALYSIS OF THE EFFECT OF COUNTER IONS S. Höfinger, 151,
INTRINSIC ISOTOPE EFFECTS-THE HOLY GRAAL OF STUDIES OF ENZYME-CATALYZED REACTIONS A. Dybala-Defratyka, R. A. Kwiecien, D. Sicinska and P. Paneth, 163,
SUICIDE INACTIVATION IN THE COENZYME B12-DEPENDENT ENZYME DIOL DEHYDRATASE Gregory M. Sandala, David M. Smith, Michelle L. Coote, and Leo Radom, 174,
SIMULATIONS OF PHOSPORYL TRANSFER REACTONS USING MULTI-SCALE QUANTUM MODELS Brent. A. Gregersen, Timothy J. Giese, Yun Liu, Evelyn Mayaan, Kwangho Nam, Kevin Range and Darrin M. York, 181,
SELECTIVITY AND AFFINITY OF MATRIX METALLOPROTEINASE INHIBITORS V. Lukacova, A. Khandelwal, Y. Zhang, D. Comez., D.M. Kroll and S. Balaz, 193,
INVESTIGATIONS OF CATALYTIC REACTION MECHANISMS OF BIOLOGICAL MACROMOLECULES BY USING FIRST PRINCIPLES AND COMBINED CLASSICAL MOLECULAR DYNAMICS METHODS Maura Boero and Masaru Tateno, 206,
Toward Drug Discovery,
CHANGING PARADIGMS IN DRUG DISCOVERY Hugo Kubinyi, 219,
A TALE OF TWO STATES: REACTIVITY OF CYTOCROME P450 ENZYMES S. Shaik, 233,
THE ROLE AND LIMITATIONS OF COMPUTATIONAL CHEMISTRY IN DRUG DISCOVERY Mike Hann, 249,
IMPROVING CATALYTIC ANTIBODIES BY MEANS OF COMPUTATIONAL TECHNIQUES Sergio Martí, Juan Andrés, Vicent Moliner, Estanislao Silla, Iñaki Timón, Juan Bertrán, 261,
THE "THEORETICAL" CHEMISTRY OF ALZHEIMER'S DISEASE: THE RADICAL MODEL Patrick Brunelle, Duilio F. Raffa, Gail A. Rickard, Rodolfo Gómez-Balderas, David A. Armstrong and Arvi Rauk, 269,
MECHANISTIC MODELING IN DRUG DISCOVERY: MMP-3 AND THE HERG CHANNEL AS EXAMPLES Jian Li, Ramkumar Rajamani, 1 Brett A. Tounge, and Charles H. Reynolds, 283,
Subject Index, 289,
CHAPTER 1
Molecular Conformation and Electronic Structure of Biomolecules
ELECTROWEAK QUANTUM CHEMISTRY AND THE DYNAMICS OF PARITY VIOLATION IN CHIRAL MOLECULES
Martin Quack ETH Zürich, Laboratory for Physical Chemistry, Wolfgang-Pauli-Str. 10, CH-8093 Zürich Switzerland
1 INTRODUCTION
In the introduction to his famous paper "Quantum Mechanics of Many Electron Systems" Paul Adrien Maurice Dirac wrote one of the most cited sentences in quantum chemistry:
"The underlying physical laws for the mathematical theory of a large part of physics and the whole of chemistry are thus completely known and the difficulty is only that the exact application of these laws leads to equations much too complicated to be soluble. It therefore becomes desirable that approximate practical methods of applying quantum mechanics should be developed, which can lead to an explanation of complex atomic systems without too much computation".
It is remarkable that the second part of this statement, which forms a reasonable starting point for modern, approximate numerical quantum chemistry and computational chemistry is only rarely cited. The more frequently cited first sentence with the strong statement about understanding "the whole of chemistry" and the small restriction "the difficulty is only", which claims that the quantum physics of the first half of the 20th century contains all basic knowledge about chemistry, is the one that seems to be liked by many theoretical chemists and physicists. It turns out, however, that this statement is incorrect. There is at least one important part of chemistry, namely stereochemistry and molecular chirality, which can be understood properly only when including the parity violating weak nuclear force in our quantum chemical theory in the framework of what we have termed "electroweak quantum chemistry, completely and fundamentally unknown at the time of Dirac's statement.
Figure 1 summarizes the modern view of the origin of the fundamental interactions as publicized on the website of a large accelerator facility (CERN) According to this view, the electromagnetic force, which is included in the "Dirac-like" ordinary quantum chemistry, leads to the Coulomb repulsion, say, between two electrons in a molecule by exchange of virtual photons. In the picture the two electrons exchanging photons are compared to the ladies on two boats throwing a ball. If we do not see the exchange of the ball, we will observe only the motion of the boats resulting from the transfer of momentum in throwing the ball, and we could interpret this as resulting from a repulsive "force" between the two ladies on the boats. Similarly, we interpret the motion of the electrons resulting from "throwing photons as field particles" as arising from the Coulomb law, which forms the basis of ordinary quantum chemistry. The Coulomb force with the 1/r potential energy law is of long range. The other forces arise similarly. The strong force with very short range (0.1 to 1 fm) mediated by the gluons is important in nuclear physics but has only indirect influence in chemistry by providing the structures of the nuclei, which enter as parameters in chemistry, but there is otherwise usually no need to retain the strong force explicitly in chemistry. The weak force, on the other hand, is mediated by the W± and Z0 Bosons of very high mass (80 to 90 Daltons, of the order of the mass of a bromine nucleus!) and short lifetime (0.26 yoctoseconds = 0.26 x 10-24 s).
This force is thus very weak and of very short range (< 0.1 fm) and one might therefore think that similar to the even weaker gravitational force (mediated by the still hypothetical graviton of spin 2) it should not contribute significantly to the...
