MOLECULAR BIOPHYSICS INTRODUCTION TO © 2003 by CRC Press LLC CRC SERIES in Pure and applied Physics Dipak Basu Editor-in-Chief PUBLISHED Titles Handbook of Particle Physics M. K. Sundaresan High-Field Electrodynamics Frederic V. Hartemann Fundamentals and Applications of Ultrasonic Waves J. David N. Cheeke Introduction to Molecular Biophysics Jack Tuszynski Michal Kurzynski © 2003 by CRC Press LLC CRC PRESS Boca Raton London New York Washington, D.C. Jack A. Tuszynski Michal Kurzynski MOLECULAR BIOPHYSICS INTRODUCTION TO © 2003 by CRC Press LLC This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. 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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identiÞcation and explanation, without intent to infringe. © 2003 by CRC Press LLC No claim to original U.S. Government works International Standard Book Number 0-8493-0039-8 Library of Congress Card Number 2002031592 Printed in the United States of America 1 2 3 4 5 6 7 8 9 0 Printed on acid-free paper Library of Congress Cataloging-in-Publication Data Tuszynski, J.A. Introduction to molecular biophysics / Jack Tuszynski, Michal Kurzynski. p. cm. — (CRC series in pure and applied physics) Includes bibliographical references and index. ISBN 0-8493-0039-8 (alk. paper) 1. Molecular biology. 2. Biophysics. I. Kurzynski, Michal. II. Title. III. Series. QH506 .T877 2003 572.8—dc21 2002031592 0039 disclaimer Page 1 Thursday, January 16, 2003 1:34 PM © 2003 by CRC Press LLC Visit the CRC Press Web site at www.crcpress.com Preface Biology has become an appealing field of study for growing numbers of physicists, mathematicians, and engineers. The reason is obvious. Extensive media coverage has made much of the world familiar with biology’s critical role on the front lines of scientific research. Former U.S. President Clinton said that the last 50 years belonged to physics and the next 50 will belong to biology. His assessment requires a slight correction: the last 300 years focused on physics. Only the last 10 or 20 concentrated on biology, but the concentration will certainly continue as technology accelerates progress. The connection between the physical and biomedical sciences developed rapidly over the past few decades, particularly after the ground-breaking discoveries in mole- cular genetics. The need clearly exists for continuing dialogues and cross-fertilization between these two groups of scientists. Ideally, neither group should attempt to “civilize” the other. As a result of the interdisciplinary nature of modern life sciences, new areas of endeavor such as mathematical biology, biophysics, computational biology, biostatistics, biological physics, theoretical biology, biological chemistry (and its older sister, biochemistry), and biomedical engineering are emerging rapidly and contributing important information to our understanding of life processes. This new appeal of biology and our growing knowledge of physical concepts that play important roles in biological activities have not proceeded without significant friction among the disciplines. The representative quotes below reflect the mutual apprehension evidentover decades (if not centuries) of co-existence. Sydney Brenner, a biologist and recent Noble Prize winner, says: Biology differs from physics in that organisms have risen by natural selection and not as the solutions to mathematical equations. Biological organisms are not made by condensation in a bag of elementary particles but by some very special processes that are, of course, consistent with the laws of physics but could not easily be directly derived from them. The trouble with physics is that its deepest pronouncements are totally incompre- hensible to almost everybody except the deepest physicists, and while they may be absolutely true, they are pretty useless tounderstand E. coli. In biology it is the detail that counts, and it counts because it is that natural selection needed to accomplish for there to be anything at all. Of course physicists have other views in this matter: There is a feeling that something is missing Molecular biology has revolu- tionized the understanding of how biological processes work, but not why. (J. Krumhansl, 1995) © 2003 by CRC Press LLC Physics studies replicas of identical atoms or molecules while in biology a single group of atoms existing in only one copy produces orderly events tuned in with each other and the environment. There is difficulty in describing life using ordi- nary laws of physics. While a new principle is needed, it should not be alien to physics. (E. Schr ¨ odinger, 1967) Molecular biology remains a largely descriptive science. Even the best known systems in biology may not be as well understood as is generally believed, which means that understanding is incomplete, and may even be misplaced. (J. Maddox, 1999) It is legitimate to ask whether the two sciences and their objects of study use operating principles at variance with each other. The principles applied in physics to mathematically describe inanimate matter focus on: • Universality • Conservation laws • Minimum energy conditions • Maximum entropy • Reproducibility On the other hand, the principles governing the biological study (seldom mathe- matical) of animate matter appear to emphasize: • Uniqueness • Diversity • Complexity • Heterogeneity • Robustness and adaptability to the environment and competition • Maximum stability • Evolutionary achievement retention (history) • Nonequilibrium (open) character • Hierarchical organization and interlocking of segments • Communication, signaling, information (perhaps even meaning and intelligence) • Repetition of motifs (all proteins are formed from 20 amino acids; all DNAs are formed from 4 nucleotides) In essence, the difference between living organisms and inanimate matter is the ability of living organisms to reproduce, adapt, and control key biological events with great precision. Cells that cannot coordinate these activities will not survive. Many molecules found in living organisms are large and complex. Proteins are the most varied and have the most diverse range of functions. Their molecular masses range from tens of thousands up to millions of hydrogen masses. Conversely, the chemi- cal subunits comprising biological molecules are not nearly so varied; essentially 20 amino acids serve as the building blocks of all proteins. © 2003 by CRC Press LLC Diversity is a simple result of a multitude of possible combinations of a finite number of structural elements. The functioning of biological systems must also be derived from this complexity. The specific organizations of complex molecular sys- tems provide specific functions but continue to be governed by fundamental physical laws. The principle of complexity begetting function is familiar to physicists and has often been referred to as an emergent phenomenon. It is characteristic of atomic systems to display new properties as they become more complex (e.g., the emergence of structural rigidity when a crystal is grown from its constituent atoms). This hierarchical, interconnected, and synchronous organization of systems that sustains life poses perhaps the greatest challenge to our intellects. However, it is hard to believe that the mysteries of life can be solved without physics. It is also doubtful that the use of standard physics rules alone will solve the mystery of life and establish its scientific basis. Our search has been greatly aided by the proliferation of sophis- ticated experimental techniques that physics has devised; they include (Parsegian, 1997): • Light microscope (resolution: 400 to 600 nm) • Electron microscope (resolution: 10 to 100 nm) • Neutron scattering (resolution: 1 to 10 Å) • X-ray crystallography (resolution: 1 Å) • Scanning tunneling microscope • Atomic force microscope • Nuclear magnetic resonance; magnetic resonance imaging • Fluorescence spectroscopy • Positron emission spectroscopy • Microwave absorption • Laser light scattering • Laser tweezers New physical concepts developed principally by nonlinear physicists are being evaluated as possible theoretical frameworks within which living systems can be better understood. These concepts involve: • Nonlinearity • Self-organization • Self-similarity • Cooperation versus competition (e.g., prey–predator models) • Collective behavior (e.g., synergetics) • Emergence and complexity The full significance of these factors will not be known until a sufficient number of test cases are closely investigated. Due to their promise, however, we have included two appendices that summarize the most important ideas and results involved in nonlinear physics and phase transitions found in many-body interacting systems. It is now generally accepted that the laws of physics apply to living organisms as much as they apply to inanimate matter. Attempts at applying physical laws to © 2003 by CRC Press LLC living systems can be traced to the early creators of modern science. Galileo analyzed the structures of animal bones using physical principles, Newton applied his optics to color perception, Volta and Cavendish studied animal electricity, and Lavoisier showed that respiration is simply another oxidative chemical reaction. Robert Mayer was inspired by physiological studies to formulate the first law of thermodynamics. A particularly fruitful area of application of physics to physiology is hydrodynamics. Poiseuille analyzed blood flow by using physics principles. Air flow in the lungs has been described consistently via the laws of aerodynamics. An important figure in the history of biophysics is German physicist and physio- logist Hermann von Helmholtz who laid the foundations for the fundamental theories of vision and hearing. A long list of physicists made large impacts on biology and physiology. We will only name a few who crossed the now-disappearing boundary between physics and biology. Delbr ¨ uck, Kendrew, von Bekesy, Crick, Meselson, Hartline, Gamow, Schr ¨ odinger, Hodgkin, Huxley, Fr ¨ ohlich, Davydov, Cooper, and Szent-Gy ¨ orgy (1972) have undoubtedly pushed the frontiers of life sciences in the direction of exact quantitative analysis. We hope and expect that the work they started will accelerate in the 21st century. Physics has proven helpful in physiology, biology, and medical research by pro- viding deeper insights into the phenomena studied by these sciences. In some fields of investigation, physics studies produced major analytic and diagnostic tools in the area of electrophysiology. Membranes of nerve cells are characterized by a voltage gradient called the action potential. The propagation of action potentials along the axons of nerve cells is the key observation made in investigating brain physiology. The theory of action potential propagation was developed by Huxley and Hodgkin, who earned a Nobel Prize for their discovery. Likewise, the discovery of the structure of DNA by Crick and Watson sparked creation of a new discipline called molecular biology, which would not have been possible without experimental and theoretical tools developed by physicists. In this case, x-ray crystallography revealed the double helix structure of DNA. More recently, investigations of DNA sequences have been pursued in the hope of revealing molecular bases for inherited diseases. Gel electrophoresis and fluo- rescent labelling are the crucial techniques perfected by physicists and biochemists for the studies of DNA sequences. Techniques that originated in physical laboratories have become standard equipment for most molecular biologists and chemists. Such devices usually start as probes of physical phenomena; they are later adapted for molecular biology and eventually transformed into common diagnostic and thera- peutic tools. X-ray machines are used to detect abnormalities. Nuclear magnetic resonance (NMR), now called magnetic resonance imaging (MRI), aids in detecting tumor growth; tumors in turn can be treated by radiation. Cardiologists use electrocardiography (ECG) to monitor heart activity; neuro- surgeons can study electrical impulses in the brain via electroencephalography (EEG). Ultrasound has applications in diagnostic (e.g., fetal development) and therapeu- tic (gall and kidney stone shattering) fields. Optical fibers are used for noninvasive examination of internal organs (Tuszynski and Dixon, 2002). This book is intended as a broad overview of molecular biophysics — the science that combines mathematics, physics, chemistry, and biology techniques to © 2003 by CRC Press LLC determine how living organisms function. The questions posed by physicists are, for example, how does the brain process and store information? How does the heart pump the blood throughout the body? How do muscles contract? How do plants extract light energy in photosynthesis? While biologists, physiologists, and geneticists work toward answering the same questions, biophysicists focus on the physics and physical chemistry of the processes. The questions apply to various levels of complexity and structural organization. On a large scale, biophysicists study how organisms develop and function. At a smaller scale, they investigate individual organs or tissues, for example, the nervous system, the immune system, or the physics of vision. Other groups quantify processes such as cell division that take place within single cells. Finally, at the finest level of organization, molecular interactions are analyzed via sophisticated experimental and theoretical techniques that overlap the areas of gene- tics, cell biology, biochemistry, and molecular physics. The hierarchies listed above are interlocked and it is not always well-advised or even possible to confine investigations to a certain level of organization. This book will serve as a guided tour through the interlocking hierarchies, starting from the smallest molecular building blocks of life and ending with a panoramic view of the evolving landscape of living forms. The objects of study belong to the realm of biology; the language of description will be physics with sprinklings of mathematics and chemistry as needed. Since life is a far-from-equilibrium process (or a complex nonlinear fabric of interdependent processes), some aspects of the book will require introduction to the key ingredients of nonlinear physics in order to convey ideas clearly. Biophysics is the study of the physics of certain complex macromolecular systems — cells and organisms — that function under conditions of insignificant temperature and pressure changes. An organism can be thought of as an intelligent, self-controlled, chemical machine that is self-regulated by molecular signals, molec- ular receptors, and transducers of information. The basic biological functional sub- systems are nucleic acids, biopolymers (peptide chains), proteins, and specialized proteins called enzymes. Biophysicists seek to understand biophysical processes by accounting for intra- molecular and intermolecular interactions, and their resulting electronic and structural conformational changes; and by studying the transfers of electrons, protons, metallic ions, and energy within biological systems. In solid state physics, such problems are solved by the methods of quantum mechanics, statistical physics, and equilibrium and nonequilibrium thermodynamics. However, since isolated biophysical systems are not found in nature, the description is complicated by the openness of living systems and their far-from-equilibrium natures. Studies of biological systems have been advanced and clearly dominated in the past by biochemistry, molecular and structural biology, and genetics. The domination accrued tremendous benefits, the most obvious of which are the availability of precise information regarding the chemical compositions of cells, macromolecules and other structural components, the discovery of the reaction pathways of the production of the synthesized components, and finally, the elucidation of the genetic code mechanism. We may be witnessing the dawn of a new era in which physics and mathematics may find a new fertile ground for the application of their exact scientific methods and © 2003 by CRC Press LLC theories. While biochemistry studies mainly atoms in direct contact with each other, many biological phenomena arise from subtler, weaker, short- and long-range forces. The solvation and desolvation problem, for example, has yet to be treated theoretically due to inherent computational limits, although it is essential to the understanding of ligand binding in physiological environments. Biological function results from specific chemical reactions and reaction cascades. Some molecules derive their functions solely from quantum mechanical interactions; others depend on classical interactions with surrounding molecules and external fields (e.g., electromagnetic fields). The main task facing theoretical biophysicists today is the investigation of the physical characteristics of biological molecules and very simple biological systems such as enzymes, functional proteins, and cellular mem- branes, while accounting for the openness of biological systems to the environment. Biological systems routinely exchange energy and matter with their environment. Many components of biological systems, such as proteins, undergo continual restruc- turing and renewal. Life is only possible because the timescale of protein stability is much longer than the timescales of the biological functions of proteins (Frauenfelder et al., 1999). Finally, we should briefly address the concept of modeling due to its importance in the advancement of science. A biological model is often understood to be simply a diagram illustrating the interrelationships of various subsystems in a process. A biochemical model is typically a diagram of several complex chemical reactions for molecular pathways and possibly a table of values for their kinetic rates. A computa- tional model is usually a computer simulation of a process with more or less arbitrary transition rules (e.g., a Monte Carlo or cellular automation model). However, a physi- cal model is expected to be a theoretical description of a process involving a number of equations of motion stemming from the first principles (if possible), testable against a range of tunable experimental conditions. It must lead to a quantitative prediction and not simply reproduce already known results. Hierarchical organization of knowledge Every branch of science is more than a collection of facts and relations. It is also a philosophy within which empirical facts and observations are organized into a unified conceptual framework providing a more or less coherent concept of reality. Since biology is the study of life and living systems, it is simultaneously the study of human beings and it can be biased by philosophical and religious beliefs. Understandably, biophilosophy has been the battleground for the two most anta- gonistic and long-lived scientific controversies between mechanism and vitalism. Mechanism holds that life is basically no different from nonlife; both are subject to the same physical and chemical laws. Living matter is simply more complex than nonliving matter. The mechanists firmly believe that life is ultimately explicable in physical and chemical terms. The vitalists, on the other hand, fervently argue that life is much more than a complex ensemble of physically reducible parts and that some life processes are not subject to normal physical and chemical laws. Consequently, © 2003 by CRC Press LLC [...]... Mesoscale History and Physics It is customary to think that unlike biology, physics is indifferent to history Point masses in Newton’s equations of motion move along periodic trajectories, then return near or to the same point in space In the case of chaotic trajectories, as stated in Poincare’s theorem in the late 19th century, point masses following chaotic motion return arbitrarily close to initial... subsystems, sensitivities to external influences, stability, adaptability, dipolar characters of constituents, modes far from equilibrium, and nonlinear responses to external perturbations © 2003 by CRC Press LLC TABLE 0.1 Dimensions of Living System Organism 1020 Atoms Thermodynamics Cell 1010 Atoms System 105 Atoms Biomolecule 103 Atoms Mesoscale Molecule 101 Atoms Quantum Chemistry Atom 1 Atom Quantum Physics... muscle contraction, movements of cilia and flagella, molecular motors, cell motility) 5 Mitochondrial processes (thermodynamics of oxidative phosphorylation, bioenergetics) 6 Photobiological processes (photosynthesis, fluorescence, chlorophyll and pigments, photoreception, membranes of photoreceptors) © 2003 by CRC Press LLC 7 Nonlinear dynamic processes (autocatalytic chemical reactions, nonlinear enzymatic... pumps 4.4 Cytoplasm 4.4.1 Osmotic pressures of cells 4.4.2 Osmotic work 4.5 Cytoskeleton: the proteins participating in cytoskeletal organization 4.5.1 Cytoskeleton 4.5.2 Biopolymers of cytoskeleton 4.5.3 Tubulin 4.5.4 Microtubules 4.5.5 Microtubule-associated proteins ... polymers are called peptides and long peptides give rise to proteins Proteins possess three-dimensional structures © 2003 by CRC Press LLC 4 Introduction to Molecular Biophysics FIGURE 1.2 In a water environment, amphiphilic molecules composed of hydrophilic (shaded) and hydrophobic (white) parts organize spontaneously into bilayers closed into three-dimensional vesicles Protein, a linear polymer of appropriately... accompanies phosphorylation of ADP to ATP with the use of sugar as a substrate has several drawbacks In addition to its low © 2003 by CRC Press LLC 8 Introduction to Molecular Biophysics (a) (b) 2H+ 3H+ H++ NADH ATP ADP + P interior 2H+ + NAD interior 2e− Q 2e− NO3 + 3H NO2 + H 2 O + 2H 2H+ FIGURE 1.5 Proton pumps transport free proton H+ across the membrane from the cell interior to its exterior at the expense... membrane and serves as an intermediary that ferries two hydrogen atoms between the two complexes At the other complex, two hydrogen atoms are again split into protons and electrons The released protons are transferred to the exterior of the membrane and the electrons and the protons from the interior of the membrane are relocated to a final acceptor site that may be a nitrate anion Thus, the created nitrite... allows us to try to reconstruct the history of the Earth, the solar system, the universe, and even time The efforts of many physicists focus on these areas of investigation today It is a general consensus that the laws of physics are well understood and it is time to apply them to systems and processes with high degrees of complexity Without a doubt, the greatest challenge for physicists today is understanding... protons in the spaces outside the original cell membrane from which they could return to the cell interiors using the proton pump of the first type (see Figure 1.3f) This pump, working in reverse, synthesizes ATP from ADP and an orthophosphate This very efficient © 2003 by CRC Press LLC 10 Introduction to Molecular Biophysics mechanism of membrane phosphorylation is universaly utilized by all present-day... transcriptases transfer it onto mRNA (d) Protein enzymes appear to be able to catalyze lactose fermentation of sugars as a result of which the pool of high-energy nucleotide (mainly triphosphates ATP) can be replenished using low energy diphosphates (mainly ADP) The amount of oxidizer (hydrogen acceptor) NAD+ remains constant; the cell interior becomes acidic (e) Proton pumps can pump H+ ions into the cell exterior . 2 3 4 5 6 7 8 9 0 Printed on acid-free paper Library of Congress Cataloging-in-Publication Data Tuszynski, J.A. Introduction to molecular biophysics / Jack Tuszynski, Michal Kurzynski. p Physics 1 Atom Cell Atom Organism System Thermodynamics Mesoscale Mesoscale Mesoscale Quantum Chemistry 10 20 Atoms 10 10 Atoms 10 5 Atoms 10 3 Atoms 10 1 Atoms Biomolecule Molecule History and Physics It is customary. MOLECULAR BIOPHYSICS INTRODUCTION TO © 2003 by CRC Press LLC CRC SERIES in Pure and applied Physics Dipak Basu Editor-in-Chief PUBLISHED Titles Handbook of