Molecules are lifeless. Yet, in appropriate complexity and number, molecules compose living things. These living systems are distinct from the inanimate world because they have certain extraordinary properties. They can grow, move, perform the incredible chemistry of metabolism, respond to stimuli from the environment, and, most significantly, replicate themselves with exceptional fidelity. The complex structure and behavior of living organisms veil the basic truth that their molecular constitution can be described and understood. The chemistry of the living cell resembles the chemistry of organic reactions. Indeed, cellular constituents or biomolecules must conform to the chemical and physical principles that govern all matter. Despite the spectacular diversity of life, the intricacy of biological structures, and the complexity of vital mechanisms, life functions are ultimately interpretable in chemical terms. Chemistry is the logic of biological phenomena.

1.1 · Distinctive Properties of Living Systems

The most obvious quality of living organisms is that they are complicated and highly organized (Figure 1.1).

Figure 1.1 • (a) Mandrill (Mandrillus sphinx), a baboon native to West Africa. (b) Tropical orchid (Bulbophyllum blumei), New Guinea. (a, Tony Angermayer/Photo Researchers, Inc.;b, Thomas C. Boydon/Marie Selby Botanical Gardens)

   (a)                                                                             (b)

For example, organisms large enough to be seen with the naked eye are composed of many cells, typically of many types. In turn, these cells possess subcellular structures or organelles, which are complex assemblies of very large polymeric molecules or macromolecules. These macromolecules themselves show an exquisite degree of organization in their intricate three-dimensional architecture, even though they are composed of simple sets of chemical building blocks, such as sugars and amino acids. Indeed, the complex three-dimensional structure of a macromolecule, known as its conformation, is a consequence of interactions between the monomeric units, according to their individual chemical properties.

            Biological structures serve functional purposes. That is, biological structures have a role in terms of the organism’s existence. From parts of organisms, such as limbs and organs, down to the chemical agents of metabolism, such as enzymes and metabolic intermediates, a biological purpose can be given for each component. Indeed, it is this functional characteristic of biological structures that separates the science of biology from studies of the inanimate world such as chemistry, physics, and geology. In biology, it is always meaningful to seek the purpose of observed structures, organizations, or patterns, that is, to ask what functional role they serve within the organism.

            Living systems are actively engaged in energy transformations. The maintenance of the highly organized structure and activity of living systems depends upon their ability to extract energy from the environment. The ultimate source of energy is the sun. Solar energy flows from photosynthetic organisms (those organisms able to capture light energy by the process of photosynthesis) through food chains to herbivores and ultimately to carnivorous predators at the apex of the food pyramid (Figure 1.2).

Figure 1.2 • The food pyramid. Photosynthetic organisms at the base capture light energy. Herbivores and carnivores derive their energy ultimately from these primary producers.  

 The biosphere is thus a system through which energy flows. Organisms capture some of this energy, be it from photosynthesis or the metabolism of food, by forming special energized biomolecules, of which ATP and NADPH are the two most prominent examples (Figure 1.3).

Figure 1.3 • ATP and NADPH, two biochemically important energy-rich compounds.  

(Commonly used abbreviations such as ATP and NADPH are defined on the inside back cover of this book.) ATP and NADPH are energized biomolecules because they represent chemically useful forms of stored energy. We explore the chemical basis of this stored energy in subsequent chapters. For now, suffice it to say that when these molecules react with other molecules in the cell, the energy released can be used to drive unfavorable processes. That is, ATP, NADPH, and related compounds are the power sources that drive the energy-requiring activities of the cell, including biosynthesis, movement, osmotic work against concentration gradients, and, in special instances, light emission (bioluminescence). Only upon death does an organism reach equilibrium with its inanimate environment. The living state is characterized by the flow of energy through the organism. At the expense of this energy flow, the organism can maintain its intricate order and activity far removed from equilibrium with its surroundings, yet exist in a state of apparent constancy over time. This state of apparent constancy, or so-called steady-state, is actually a very dynamic condition: energy and material are consumed by the organism and used to maintain its stability and order. In contrast, inanimate matter, as exemplified by the universe in totality, is moving to a condition of increasing disorder or, in thermodynamic terms, maximum entropy.             Living systems have a remarkable capacity for self-replication. Generation after generation, organisms reproduce virtually identical copies of themselves. This self-replication can proceed by a variety of mechanisms, ranging from simple division in bacteria to sexual reproduction in plants and animals, but in every case, it is characterized by an astounding degree of fidelity (Figure 1.4).

   (a)                                                                                                                                                                                     (b)

Figure 1.4 • Organisms resemble their parents. (a) Reg Garrett with sons Robert, Jeffrey, Randal, and grandson Jackson. (b) Orangutan with infant. (c) The Grishams: Andrew, Rosemary, Charles, Emily, and David. (a, William W. Garrett, II; b, Randal Harrison Garrett; c, Charles Y. Sipe)

   (c)

Indeed, if the accuracy of self-replication were significantly greater, the evolution of organisms would be hampered. This is so because evolution depends upon natural selection operating on individual organisms that vary slightly in their fitness for the environment. The fidelity of self-replication resides ultimately in the chemical nature of the genetic material. This substance consists of polymeric chains of deoxyribonucleic acid, or DNA, which are structurally complementary to one another (Figure 1.5).

Figure 1.5 • The DNA double heli x. Two complementary polynucleotide chains running in opposite directions can pair through hydrogen bonding between their nitrogenous bases. Their complementary nucleotide sequences give rise to structural complementarity.

These molecules can generate new copies of themselves in a rigorously executed polymerization process that ensures a faithful reproduction of the original DNA strands. In contrast, the molecules of the inanimate world lack this capacity to replicate. A crude mechanism of replication, or specification of unique chemical structure according to some blueprint, must have existed at life’s origin. This primordial system no doubt shared the property of structural complementarity (see later section) with the highly evolved patterns of replication prevailing today.

1.2 · Biomolecules: The Molecules of Life

The elemental composition of living matter differs markedly from the relative abundance of elements in the earth’s crust (Table 1.1).

Hydrogen, oxygen, carbon, and nitrogen constitute more than 99% of the atoms in the human body, with most of the H and O occurring as H₂O. Oxygen, silicon, aluminum, and iron are the most abundant atoms in the earth’s crust, with hydrogen, carbon, and nitrogen being relatively rare (less than 0.2% each). Nitrogen as dinitrogen (N₂) is the predominant gas in the atmosphere, and carbon dioxide (CO₂) is present at a level of 0.05%, a small but critical amount. Oxygen is also abundant in the atmosphere and in the oceans. What property unites H, O, C, and N and renders these atoms so suitable to the chemistry of life? It is their ability to form covalent bonds by electron-pair sharing. Furthermore, H, C, N, and O are among the lightest elements of the periodic table capable of forming such bonds (Figure 1.6).

Figure 1.6 • Covalent bond formation by e^- pair sharing.

Because the strength of covalent bonds is inversely proportional to the atomic weights of the atoms involved, H, C, N, and O form the strongest covalent bonds. Two other covalent bond-forming elements, phosphorus (as phosphate -OPO₃^2- derivatives) and sulfur, also play important roles in biomolecules.

Biomolecules Are Carbon Compounds

All biomolecules contain carbon. The prevalence of C is due to its unparalleled versatility in forming stable covalent bonds by electron-pair sharing. Carbon can form as many as four such bonds by sharing each of the four electrons in its outer shell with electrons contributed by other atoms. Atoms commonly found in covalent linkage to C are C itself, H, O, and N. Hydrogen can form one such bond by contributing its single electron to formation of an electron pair. Oxygen, with two unpaired electrons in its outer shell, can participate in two covalent bonds, and nitrogen, which has three unshared electrons, can form three such covalent bonds. Furthermore, C, N, and O can share two electron pairs to form double bonds with one another within biomolecules, a property that enhances their chemical versatility. Carbon and nitrogen can even share three electron pairs to form triple bonds.
            Two properties of carbon covalent bonds merit particular attention. One is the ability of carbon to form covalent bonds with itself. The other is the tetrahedral nature of the four covalent bonds when carbon atoms form only single bonds. Together these properties hold the potential for an incredible variety of linear, branched, and cyclic compounds of C. This diversity is multiplied further by the possibilities for including N, O, and H atoms in these compounds (Figure 1.7). We can therefore envision the ability of C to generate complex structures in three dimensions. These structures, by virtue of appropriately included N, O, and H atoms, can display unique chemistries suitable to the living state. Thus, we may ask, is there any pattern or underlying organization that brings order to this astounding potentiality?

  Figure 1.7 • Examples of the versatility of C—C bonds in building complex structures: linear aliphatic, cyclic, branched, and planar.  

1.3 · A Biomolecular Hierarchy: Simple Molecules Are the Units for Building Complex Structures
Examination of the chemical composition of cells reveals a dazzling variety of organic compounds covering a wide range of molecular dimensions (Table 1.2). As this complexity is sorted out and biomolecules are classified according to the similarities in size and chemical properties, an organizational pattern emerges. The molecular constituents of living matter do not reflect randomly the infinite possibilities for combining C, H, O, and N atoms. Instead, only a limited set of the many possibilities is found, and these collections share certain properties essential to the establishment and maintenance of the living state. The most prominent aspect of biomolecular organization is that macromolecular structures are constructed from simple molecules according to a hierarchy of increasing structural complexity. What properties do these biomolecules possess that make them so appropriate for the condition of life?  

Metabolites and Macromolecules
The major precursors for the formation of biomolecules are water, carbon dioxide, and three inorganic nitrogen compounds—ammonium (NH⁴⁺), nitrate (NO₃^-), and dinitrogen (N₂). Metabolic processes assimilate and transform these inorganic precursors through ever more complex levels of biomolecular order (Figure 1.8).

Figure 1.8 • Molecular organization in the cell is a hierarchy.

  In the first step, precursors are converted to metabolites, simple organic compounds that are intermediates in cellular energy transformation and in the biosynthesis of various sets of building blocks: amino acids, sugars, nucleotides, fatty acids, and glycerol. By covalent linkage of these building blocks, the macromolecules are constructed: proteins, polysaccharides, polynucleotides (DNA and RNA), and lipids. (Strictly speaking, lipids contain relatively few building blocks and are therefore not really polymeric like other macromolecules; however, lipids are important contributors to higher levels of complexity.) Interactions among macromolecules lead to the next level of structural organization, supramolecular complexes. Here, various members of one or more of the classes of macromolecules come together to form specific assemblies serving important subcellular functions. Examples of these supramolecular assemblies are multifunctional enzyme complexes, ribosomes, chromosomes, and cytoskeletal elements. For example, a eukaryotic ribosome contains four different RNA molecules and at least 70 unique proteins. These supramo-lecular assemblies are an interesting contrast to their components because their structural integrity is maintained by noncovalent forces, not by covalent bonds. These noncovalent forces include hydrogen bonds, ionic attractions, van der Waals forces, and hydrophobic interactions between macromolecules. Such forces maintain these supramolecular assemblies in a highly ordered functional state. Although noncovalent forces are weak (less than 40 kJ/mol), they are numerous in these assemblies and thus can collectively maintain the essential architecture of the supramolecular complex under conditions of temperature, pH, and ionic strength that are consistent with cell life.

Organelles
The next higher rung in the hierarchical ladder is occupied by the organelles, entities of considerable dimensions compared to the cell itself. Organelles are found only in eukaryotic cells, that is, the cells of “higher” organisms (eukaryotic cells are described in Section 1.5). Several kinds, such as mitochondria and chloroplasts, evolved from bacteria that gained entry to the cytoplasm of early eukaryotic cells. Organelles share two attributes: they are cellular inclusions, usually membrane bounded, and are dedicated to important cellular tasks. Organelles include the nucleus, mitochondria, chloroplasts, endoplasmic reticulum, Golgi apparatus, and vacuoles as well as other relatively small cellular inclusions, such as peroxisomes, lysosomes, and chromoplasts. The nucleus is the repository of genetic information as contained within the linear sequences of nucleotides in the DNA of chromosomes. Mitochondria are the “power plants” of cells by virtue of their ability to carry out the energy-releasing aerobic metabolism of carbohydrates and fatty acids, capturing the energy in metabolically useful forms such as ATP. Chloroplasts endow cells with the ability to carry out photosynthesis. They are the biological agents for harvesting light energy and transforming it into metabolically useful chemical forms.

Membranes
Membranes define the boundaries of cells and organelles. As such, they are not easily classified as supramolecular assemblies or organelles, although they share the properties of both. Membranes resemble supramolecular complexes in their construction because they are complexes of proteins and lipids maintained by noncovalent forces. Hydrophobic interactions are particularly important in maintaining membrane structure. Hydrophobic interactions arise because water molecules prefer to interact with each other rather than with nonpolar substances. The presence of nonpolar molecules lessens the range of opportunities for water-water interaction by forcing the water molecules into ordered arrays around the nonpolar groups. Such ordering can be minimized if the individual nonpolar molecules redistribute from a dispersed state in the water into an aggregated organic phase surrounded by water. The spontaneous assembly of membranes in the aqueous environment where life arose and exists is the natural result of the hydrophobic (“water-fearing”) character of their lipids and proteins. Hydrophobic interactions are the creative means of membrane formation and the driving force that presumably established the boundary of the first cell. The membranes of organelles, such as nuclei, mitochondria, and chloroplasts, differ from one another, with each having a characteristic protein and lipid composition suited to the organelle’s function. Furthermore, the creation of discrete volumes or compartments within cells is not only an inevitable consequence of the presence of membranes but usually an essential condition for proper organellar function.

The Unit of Life Is the Cell
The cell is characterized as the unit of life, the smallest entity capable of displaying the attributes associated uniquely with the living state: growth, metabolism, stimulus response, and replication. In the previous discussions, we explicitly narrowed the infinity of chemical complexity potentially available to organic life, and we previewed an organizational arrangement, moving from simple to complex, that provides interesting insights into the functional and structural plan of the cell. Nevertheless, we find no obvious explanation within these features for the living characteristics of cells. Can we find other themes represented within biomolecules that are explicitly chemical yet anticipate or illuminate the living condition?

1.4 · Properties of Biomolecules Reflect Their Fitness to the Living Condition

If we consider what attributes of biomolecules render them so fit as components of growing, replicating systems, several biologically relevant themes of structure and organization emerge. Furthermore, as we study biochemistry, we will see that these themes serve as principles of biochemistry. Prominent among them is the necessity for information and energy in the maintenance of the living state. Some biomolecules must have the capacity to contain the information or “recipe” of life. Other biomolecules must have the capacity to translate this information so that the blueprint is transformed into the functional, organized structures essential to life. Interactions between these structures are the processes of life. An orderly mechanism for abstracting energy from the environment must also exist in order to obtain the energy needed to drive these processes. What properties of biomolecules endow them with the potential for such remarkable qualities?

Biological Macromolecules and Their Building Blocks Have a “Sense” or Directionality The macromolecules of cells are built of units—amino acids in proteins, nucleotides in nucleic acids, and carbohydrates in polysaccharides—that have structural polarity. That is, these molecules are not symmetrical, and so they can be thought of as having a “head” and a “tail.” Polymerization of these units to form macromolecules occurs by head-to-tail linear connections. Because of this, the polymer also has a head and a tail, and hence, the macromolecule has a “sense” or direction to its structure (Figure 1.9).

Figure 1.9 • (a) Amino acids build proteins by connecting the a -carboxyl C atom of one amino acid to the a -amino N atom of the next amino acid in line. (b) Polysaccharides are built by combining the C-1 of one sugar to the C-4 O of the next sugar in the polymer. (c) Nucleic acids are polymers of nucleotides linked by bonds between the 3 ¢ -OH of the ribose ring of one nucleotide to the 5 ¢ -PO₄ of its neighboring nucleotide. All three of these polymerization processes involve bond formations accompanied by the elimination of water (dehydration synthesis reactions).

Biological Macromolecules Are Informational
Because biological macromolecules have a sense to their structure, the sequential order of their component building blocks, when read along the length of the molecule, has the capacity to specify information in the same manner that the letters of the alphabet can form words when arranged in a linear sequence (Figure 1.10).

Figure 1.10 • The sequence of monomeric units in a biological polymer has the potential to contain information if the diversity and order of the units are not overly simple or repetitive. Nucleic acids and proteins are information-rich molecules; polysaccharides are not.

Not all biological macromolecules are rich in information. Polysaccharides are often composed of the same sugar unit repeated over and over, as in cellulose or starch, which are homopolymers of many glucose units. On the other hand, proteins and polynucleotides are typically composed of building blocks arranged in no obvious repetitive way; that is, their sequences are unique, akin to the letters and punctuation that form this descriptive sentence. In these unique sequences lies meaning. To discern the meaning, however, requires some mechanism for recognition.

Biomolecules Have Characteristic Three-Dimensional Architecture
The structure of any molecule is a unique and specific aspect of its identity. Molecular structure reaches its pinnacle in the intricate complexity of biological macromolecules, particularly the proteins. Although proteins are linear sequences of covalently linked amino acids, the course of the protein chain can turn, fold, and coil in the three dimensions of space to establish a specific, highly ordered architecture that is an identifying characteristic of the given protein molecule (Figure 1.11).

  Figure 1.11 • Three-dimensional space-filling representation of part of a protein molecule, the antigen-binding domain of immunoglobulin G (IgG). Immunoglobulin G is a major type of circulating antibody. Each of the spheres represents an atom in the structure.  

Weak Forces Maintain Biological Structure and Determine Biomolecular Interactions
Covalent bonds hold atoms together so that molecules are formed. In contrast, weak chemical forces or noncovalent bonds, (hydrogen bonds, van der Waals forces, ionic interactions, and hydrophobic interactions) are intramolecular or intermolecular attractions between atoms. None of these forces, which typically range from 4 to 30 kJ/mol, are strong enough to bind free atoms together (Table 1.3). The average kinetic energy of molecules at 25°C is 2.5 kJ/mol, so the energy of weak forces is only several times greater than the dissociating tendency due to thermal motion of molecules. Thus, these weak forces create interactions that are constantly forming and breaking at physiological temperature, unless by cumulative number they impart stability to the structures generated by their collective action. These weak forces merit further discussion because their attributes profoundly influence the nature of the biological structures they build.

Van der Waals Attractive Forces
Van der Waals forces are the result of induced electrical interactions between closely approaching atoms or molecules as their negatively-charged electron clouds fluctuate instantaneously in time. These fluctuations allow attractions to occur between the positively charged nuclei and the electrons of nearby atoms. Van der Waals interactions include dipole-dipole interactions, whose interaction energies decrease as 1/r³; dipole-induced dipole interactions, which fall off as 1/ r^5; and induced dipole-induced dipole interactions, often called dispersion or London dispersion forces, which diminish as 1/ r⁶. Dispersion forces contribute to the attractive intermolecular forces between all molecules, even those without permanent dipoles, and are thus generally more important than dipole-dipole attractions. Van der Waals attractions operate only over a limited interatomic distance and are an effective bonding interaction at physiological temperatures only when a number of atoms in a molecule can interact with several atoms in a neighboring molecule. For this to occur, the atoms on interacting molecules must pack together neatly. That is, their molecular surfaces must possess a degree of structural complementarity (Figure 1.12).

Figure 1.12 • Van der Waals packing is enhanced in molecules that are structurally complementary. Gln¹²¹ represents a surface protuberance on the protein lysozyme. This protuberance fits nicely within a pocket (formed by Tyr¹⁰¹, Tyr³², Phe⁹¹, and Trp⁹²) in the antigen-binding domain of an antibody raised against lysozyme. (See also Figure 1.16.) (a) A space-filling representation. (b) A ball-and-stick model. (From Science 233:751 (1986), figure 5.)

            At best, van der Waals interactions are weak and individually contribute 0.4 to 4.0 kJ/mol of stabilization energy. However, the sum of many such interactions within a macromolecule or between macromolecules can be substantial. For example, model studies of heats of sublimation show that each methylene group in a crystalline hydrocarbon accounts for 8 kJ, and each C-H group in a benzene crystal contributes 7 kJ of van der Waals energy per mole. Calculations indicate that the attractive van der Waals energy between the enzyme lysozyme and a sugar substrate that it binds is about 60 kJ/mol.

            When two atoms approach each other so closely that their electron clouds interpenetrate, strong repulsion occurs. Such repulsive van der Waals forces follow an inverse 12th-power dependence on r (1/ r¹²), as shown in Figure 1.13.

 Between the repulsive and attractive domains lies a low point in the potential curve. This low point defines the distance known as the van der Waals contact distance, which is the interatomic distance that results if only van der Waals forces hold two atoms together. The limit of approach of two atoms is determined by the sum of their van der Waals radii (Table 1.4).

Hydrogen Bonds
Hydrogen bonds form between a hydrogen atom covalently bonded to an electronegative atom (such as oxygen or nitrogen) and a second electronegative atom that serves as the hydrogen bond acceptor. Several important biological examples are given in Figure 1.14.

Figure 1.14 • Some of the biologically important H bonds and functional groups that serve as H bond donors and acceptors.

Hydrogen bonds, at a strength of 12 to 30 kJ/mol, are stronger than van der Waals forces and have an additional property: H bonds tend to be highly directional, forming straight bonds between donor, hydrogen, and acceptor atoms. Hydrogen bonds are also more specific than van der Waals interactions because they require the presence of complementary hydrogen donor and acceptor groups.

Ionic Interactions
Ionic interactions are the result of attractive forces between oppositely charged polar functions, such as negative carboxyl groups and positive amino groups (Figure 1.15).   

Figure 1.15 • Ionic bonds in biological molecules.  

These electrostatic forces average about 20 kJ/mol in aqueous solutions. Typically, the electrical charge is radially distributed, and so these interactions may lack the directionality of hydrogen bonds or the precise fit of van der Waals interactions. Nevertheless, because the opposite charges are restricted to sterically defined positions, ionic interactions can impart a high degree of structural specificity.
            The strength of electrostatic interactions is highly dependent on the nature of the interacting species and the distance, r, between them. Electrostatic interactions may involve ions (species possessing discrete charges), permanent dipoles (having a permanent separation of positive and negative charge), and induced dipoles (having a temporary separation of positive and negative charge induced by the environment). Between two ions, the energy falls off as 1/r. The interaction energy between permanent dipoles falls off as 1/ r^3, whereas the energy between an ion and an induced dipole falls off as 1/ r⁴.

Hydrophobic Interactions
Hydrophobic interactions are due to the strong tendency of water to exclude nonpolar groups or molecules (see Chapter 2). Hydrophobic interactions arise not so much because of any intrinsic affinity of nonpolar substances for one another (although van der Waals forces do promote the weak bonding of nonpolar substances), but because water molecules prefer the stronger interactions that they share with one another, compared to their interaction with nonpolar molecules. Hydrogen-bonding interactions between polar water molecules can be more varied and numerous if nonpolar molecules coalesce to form a distinct organic phase. This phase separation raises the entropy of water because fewer water molecules are arranged in orderly arrays around individual nonpolar molecules. It is these preferential interactions between water molecules that “exclude” hydrophobic substances from aqueous solution and drive the tendency of nonpolar molecules to cluster together. Thus, nonpolar regions of biological macromolecules are often buried in the molecule’s interior to exclude them from the aqueous milieu. The formation of oil droplets as hydrophobic nonpolar lipid molecules coalesce in the presence of water is an approximation of this phenomenon. These tendencies have important consequences in the creation and maintenance of the macromolecular structures and supramolecular assemblies of living cells.

Structural Complementarity Determines Biomolecular Interactions
Structural complementarity is the means of recognition in biomolecular interactions. The complicated and highly organized patterns of life depend upon the ability of biomolecules to recognize and interact with one another in very specific ways. Such interactions are fundamental to metabolism, growth, replication, and other vital processes. The interaction of one molecule with another, a protein with a metabolite, for example, can be most precise if the structure of one is complementary to the structure of the other, as in two connecting pieces of a puzzle or, in the more popular analogy for macromolecules and their ligands, a lock and its key (Figure 1.16).

(click chime icon for animation of figure a)
Figure 1.16 • Structural complementarity: the pieces of a puzzle, the lock and its key, a biological macromolecule and its ligand—an antigen–antibody complex. (a) The antigen on the right (green) is a small protein, lysozyme, from hen egg white. The part of the antibody molecule (IgG) shown on the left in blue and yellow includes the antigen-binding domain. (b) This domain has a pocket that is structurally complementary to a surface protuberance (Gln¹²¹, shown in red between antigen and antigen-binding domain) on the antigen. (See also Figure 1.12.)(photos, courtesy of Professor Simon E. V. Philips)

This principle of structural complementarity is the very essence of biomolecular recognition. Structural complementarity is the significant clue to understanding the functional properties of biological systems. Biological systems from the macromolecular level to the cellular level operate via specific molecular recognition mechanisms based on structural complementarity: a protein recognizes its specific metabolite, a strand of DNA recognizes its complementary strand, sperm recognize an egg. All these interactions involve structural complementarity between molecules.

Biomolecular Recognition Is Mediated by Weak Chemical Forces
The biomolecular recognition events that occur through structural complementarity are mediated by the weak chemical forces previously discussed. It is important to realize that, because these interactions are sufficiently weak, they are readily reversible. Consequently, biomolecular interactions tend to be transient; rigid, static lattices of biomolecules that might paralyze cellular activities are not formed. Instead, a dynamic interplay occurs between metabolites and macromolecules, hormones and receptors, and all the other participants instrumental to life processes. This interplay is initiated upon specific recognition between complementary molecules and ultimately culminates in unique physiological activities. Biological function is achieved through mechanisms based on structural complementarity and weak chemical interactions.
            This principle of structural complementarity extends to higher interactions essential to the establishment of the living condition. For example, the formation of supramolecular complexes occurs because of recognition and interaction between their various macromolecular components, as governed by the weak forces formed between them. If a sufficient number of weak bonds can be formed, as in macromolecules complementary in structure to one another, larger structures assemble spontaneously. The tendency for nonpolar molecules and parts of molecules to come together through hydrophobic interactions also promotes the formation of supramolecular assemblies. Very complex subcellular structures are actually spontaneously formed in an assembly process that is driven by weak forces accumulated through structural complementarity.

Weak Forces Restrict Organisms to a Narrow Range of Environmental Conditions
The central role of weak forces in biomolecular interactions restricts living systems to a narrow range of physical conditions. Biological macromolecules are functionally active only within a narrow range of environmental conditions, such as temperature, ionic strength, and relative acidity. Extremes of these conditions disrupt the weak forces essential to maintaining the intricate structure of macromolecules. The loss of structural order in these complex macromolecules, so-called denaturation, is accompanied by loss of function (Figure 1.17).

  Figure 1.17 • Denaturation and renaturation of the intricate structure of a protein.

As a consequence, cells cannot tolerate reactions in which large amounts of energy are released. Nor can they generate a large energy burst to drive energy-requiring processes. Instead, such transformations take place via sequential series of chemical reactions whose overall effect achieves dramatic energy changes, even though any given reaction in the series proceeds with only modest input or release of energy (Figure 1.18).

Figure 1.18 • Metabolism is the organized release or capture of small amounts of energy in processes whose overall change in energy is large. (a) For example, the combustion of glucose by cells is a major pathway of energy production, with the energy captured appearing as 30 to 38 equivalents of ATP, the principal energy-rich chemical of cells. The ten reactions of glycolysis, the nine reactions of the citric acid cycle, and the successive linked reactions of oxidative phosphorylation release the energy of glucose in a stepwise fashion and the small “packets” of energy appear in ATP. (b) Combustion of glucose in a bomb calorimeter results in an uncontrolled, explosive release of energy in its least useful form, heat.

These sequences of reactions are organized to provide for the release of useful energy to the cell from the breakdown of food or to take such energy and use it to drive the synthesis of biomolecules essential to the living state. Collectively, these reaction sequences constitute cellular metabolism—the ordered reaction pathways by which cellular chemistry proceeds and biological energy transformations are accomplished.

Enzymes
The sensitivity of cellular constituents to environmental extremes places another constraint on the reactions of metabolism. The rate at which cellular reactions proceed is a very important factor in maintenance of the living state. However, the common ways chemists accelerate reactions are not available to cells; the temperature cannot be raised, acid or base cannot be added, the pressure cannot be elevated, and concentrations cannot be dramatically increased. Instead, biomolecular catalysts mediate cellular reactions. These catalysts, called enzymes, accelerate the reaction rates many orders of magnitude and, by selecting the substances undergoing reaction, determine the specific reaction taking place. Virtually every metabolic reaction is served by an enzyme whose sole biological purpose is to catalyze its specific reaction (Figure 1.19).

Figure 1.19 • Carbonic anhydrase, a representative enzyme, and the reaction that it catalyzes. Dissolved carbon dioxide is slowly hydrated by water to form bicarbonate ion and H⁺: At 20°C, the rate constant for this uncatalyzed reaction, k_uncat, is 0.03/sec. In the presence of the enzyme carbonic anhydrase, the rate constant for this reaction, k_cat, is 10⁶/sec. Thus carbonic anhydrase accelerates the rate of this reaction 3.3 x 10⁷ times. Carbonic anhydrase is a 29-kD protein.

Metabolic Regulation Is Achieved by Controlling the Activity of Enzymes
Thousands of reactions mediated by an equal number of enzymes are occurring at any given instant within the cell. Metabolism has many branch points, cycles, and interconnections, as a glance at a metabolic pathway map reveals (Figure 1.20).

Figure 1.20 • Reproduction of a metabolic map. (Courtesy of D. E. Nicholson, University of Leeds and Sigma Chemical Co., St. Louis, MO.)

All of these reactions, many of which are at apparent cross-purposes in the cell, must be fine-tuned and integrated so that metabolism and life proceed harmoniously. The need for metabolic regulation is obvious. This metabolic regulation is achieved through controls on enzyme activity so that the rates of cellular reactions are appropriate to cellular requirements.
            Despite the organized pattern of metabolism and the thousands of enzymes required, cellular reactions nevertheless conform to the same thermodynamic principles that govern any chemical reaction. Enzymes have no influence over energy changes (the thermodynamic component) in their reactions. Enzymes only influence reaction rates. Thus, cells are systems that take in food, release waste, and carry out complex degradative and biosynthetic reactions essential to their survival while operating under conditions of essentially constant temperature and pressure and maintaining a constant internal environment (homeostasis) with no outwardly apparent changes. Cells are open thermodynamic systems exchanging matter and energy with their environment and functioning as highly regulated isothermal chemical engines.

1.5 · Organization and Structure of Cells

All living cells fall into one of two broad categories—prokaryotic and eukaryotic. The distinction is based on whether or not the cell has a nucleus. Prokaryotes are single-celled organisms that lack nuclei and other organelles; the word is derived from pro meaning “prior to” and karyot meaning  “nucleus.” In conventional biological classification schemes, prokaryotes are grouped together as members of the kingdom Monera, represented by bacteria and cyanobacteria (formerly called blue-green algae). The other four living kingdoms are all eukaryotes—the single-celled Protists, such as amoebae, and all multicellular life forms, including the Fungi, Plant, and Animal kingdoms. Eukaryotic cells have true nuclei and other organelles such as mitochondria, with the prefix eu meaning “true.”

Early Evolution of Cells
Until recently, most biologists accepted the idea that eukaryotes evolved from the simpler prokaryotes in some linear progression from simple to complex over the course of geological time. Contemporary evidence favors the view that present-day organisms are better grouped into three classes or lineages: eukaryotes and two prokaryotic groups, the eubacteria and the archaea (formerly designated as archaebacteria). All are believed to have evolved approximately 3.5 billion years ago from a common ancestral form called the progenote. It is now understood that eukaryotic cells are, in reality, composite cells derived from various prokaryotic contributions. Thus, the dichotomy between prokaryotic cells and eukaryotic cells, although convenient, is an artificial distinction.
            Despite the great diversity in form and function, cells and organisms share a common biochemistry. This commonality, although long established, has received further validation through whole genome sequencing, or the determination of the complete nucleotide sequence within the DNA of an organism. For example, the recently sequenced genome of the archaeon Methanococcus jannaschii shows 44% similarity to known genes in eubacteria and eukaryotes, yet 56% of its genes are new to science. Whole genome sequencing is revolutionizing biochemistry as the protein-coding sequences of newly revealed genes outpace our understanding of what the proteins are and what they do.

Structural Organization of Prokaryotic Cells
Among prokaryotes (the simplest cells), most known species are eubacteria and they form a widely spread group. Certain of them are pathogenic to humans. The archaea are remarkable because they can be found in unusual environments where other cells cannot survive. Archaea include the thermoacidophiles (heat- and acid-loving bacteria) of hot springs, the halophiles (salt-loving bacteria) of salt lakes and ponds, and the methanogens (bacteria that generate methane from CO₂ and H₂). Prokaryotes are typically very small, on the order of several microns in length, and are usually surrounded by a rigid cell wall that protects the cell and gives it its shape. The characteristic structural organization of a prokaryotic cell is depicted in Figure 1.21.

  Figure 1.21 • This bacterium is Escherichia coli, a member of the coliform group of bacteria that colonize the intestinal tract of humans. E. coli organisms have rather simple nutritional requirements. They grow and multiply quite well if provided with a simple carbohydrate source of energy (such as glucose), ammonium ions as a source of nitrogen, and a few mineral salts. The simple nutrition of this “lower” organism means that its biosynthetic capacities must be quite advanced. When growing at 37°C on a rich organic medium, E. coli cells divide every 20 minutes. Subcellular features include the cell wall, plasma membrane, nuclear region, ribosomes, storage granules, and cytosol (Table 1.5). (photo, Martin Rotker/Phototake, Inc.; inset photo, David M. Phillips/The Population Council/Science Source/Photo Researchers, Inc.)

            Prokaryotic cells have only a single membrane, the plasma membrane or cell membrane. Because they have no other membranes, prokaryotic cells contain no nucleus or organelles. Nevertheless, they possess a distinct nuclear area where a single circular chromosome is localized, and some have an internal membranous structure called a mesosome that is derived from and continuous with the cell membrane. Reactions of cellular respiration are localized on these membranes. In photosynthetic prokaryotes such as the cyanobacteria, flat, sheetlike membranous structures called lamellae are formed from cell membrane infoldings. These lamellae are the sites of photosynthetic activity, but in prokaryotes, they are not contained within plastids, the organelles of photosynthesis found in higher plant cells. Prokaryotic cells also lack a cytoskeleton; the cell wall maintains their structure. Some bacteria have , single, long filaments used for motility. Prokaryotes largely reproduce by asexual division, although sexual exchanges can occur. Table 1.5 lists the major features of prokaryotic cells. Table 1.6 lists some of the many human illnesses caused by prokaryotes.

Table 1.6
Some Human Disease Caused by Prokaryotes
Disease		Causative Organism
Tetanus (lockjaw)		Clostridium tetani
Botulism		Clostridium botulinum
Whooping cough		Bordetella pertussis
Cholera		Vibrio cholerae
Bubonic plague		Yersinia pestis
Diphtheria		Corynebacterium diphtheriae
Tuberculosis		Mycobacterium tuberculosis
Leprosy		Mycobacterium leprae
Gonorrhea		Neisseria gonorrhoeae

  Structural Organization of Eukaryotic Cells
In comparison to prokaryotic cells, eukaryotic cells are much greater in size, typically having cell volumes 10³ to 10⁴ times larger. Also, they are much more complex. These two features require that eukaryotic cells partition their diverse metabolic processes into organized compartments, with each compartment dedicated to a particular function. A system of internal membranes accomplishes this partitioning. A typical animal cell is shown in Figure 1.22;

Figure 1.22 • This figure diagrams a rat liver cell, a typical higher animal cell in which the characteristic features of animal cells are evident, such as a nucleus, nucleolus, mitochondria, Golgi bodies, lysosomes, and endoplasmic reticulum (ER). Microtubules and the network of filaments constituting the cytoskeleton are also depicted. (photos, top, Dwight R. Kuhn/Visuals Unlimited; middle, D.W. Fawcett/Visuals Unlimited; bottom, Keith Porter/Photo Researchers, Inc.)

a typical plant cell in Figure 1.23.

Figure 1.23 • This figure diagrams a cell in the leaf of a higher plant. The cell wall, membrane, nucleus, chloroplasts, mitochondria, vacuole, ER, and other characteristic features are shown. (photos, top, middle, Dr. Dennis Kunkel/Phototake, NYC; bottom, Biophoto Associates)

    Tables 1.7 and 1.8 list the major features of a typical animal cell and a higher plant cell, respectively.

            Eukaryotic cells possess a discrete, membrane-bounded nucleus, the repository of the cell’s genetic material, which is distributed among a few or many chromosomes. During cell division, equivalent copies of this genetic material must be passed to both daughter cells through duplication and orderly partitioning of the chromosomes by the process known as mitosis. Like prokaryotic cells, eukaryotic cells are surrounded by a plasma membrane. Unlike prokaryotic cells, eukaryotic cells are rich in internal membranes that are differentiated into specialized structures such as the endoplasmic reticulum (ER) and the Golgi apparatus. Membranes also surround certain organelles (mitochondria and chloroplasts, for example) and various vesicles, including vacuoles, lysosomes, and peroxisomes. The common purpose of these membranous partitionings is the creation of cellular compartments that have specific, organized metabolic functions, such as the mitochondrion’s role as the principal site of cellular energy production. Eukaryotic cells also have a cytoskeleton composed of arrays of filaments that give the cell its shape and its capacity to move. Some eukaryotic cells also have long projections on their surface—cilia or flagella—which provide propulsion.

1.6 · Viruses Are Supramolecular Assemblies Acting as Cell Parasites Viruses are supramolecular complexes of nucleic acid, either DNA or RNA, encapsulated in a protein coat and, in some instances, surrounded by a membrane envelope (Figure 1.24).

The bits of nucleic acid in viruses are, in reality, mobile elements of genetic information. The protein coat serves to protect the nucleic acid and allows it to gain entry to the cells that are its specific hosts. Viruses unique for all types of cells are known. Viruses infecting bacteria are called bacteriophages (“bacteria eaters”); different viruses infect animal cells and plant cells. Once the nucleic acid of a virus gains access to its specific host, it typically takes over the metabolic machinery of the host cell, diverting it to the production of virus particles. The host metabolic functions are subjugated to the synthesis of viral nucleic acid and proteins. Mature virus particles arise by encapsulating the nucleic acid within a protein coat called the capsid. Viruses are thus supramolecular assemblies that act as parasites of cells (Figure 1.25).

Figure 1.25 • The virus life cycle. Viruses are mobile bits of genetic information encapsulated in a protein coat. The genetic material can be either DNA or RNA. Once this genetic material gains entry to its host cell, it takes over the host machinery for macromolecular synthesis and subverts it to the synthesis of viral-specific nucleic acids and proteins. These virus components are then assembled into mature virus particles that are released from the cell. Often, this parasitic cycle of virus infection leads to cell death and disease.

            Often, viruses cause the lysis of the cells they infect. It is their cytolytic properties that are the basis of viral disease. In certain circumstances, the viral genetic elements may integrate into the host chromosome and become quiescent. Such a state is termed lysogeny. Typically, damage to the host cell activates the replicative capacities of the quiescent viral nucleic acid, leading to viral propagation and release. Some viruses are implicated in transforming cells into a cancerous state, that is, in converting their hosts to an unregulated state of cell division and proliferation. Because all viruses are heavily dependent on their host for the production of viral progeny, viruses must have arisen after cells were established in the course of evolution. Presumably, the first viruses were fragments of nucleic acid that developed the ability to replicate independently of the chromosome and then acquired the necessary genes enabling protection, autonomy, and transfer between cells.