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GaloreRhodium8872

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The University of Kansas

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biochemistry protein structure organic chemistry biology

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This document details the foundational concepts of biochemistry, focusing on the structure and function of proteins. It provides an overview of the chemistry of living organisms, specifically highlighting the unique characteristics of proteins as polymers of amino acids.

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# Chapter One: The Rules of the Game ## 1.1 The Makeup of Living Organisms - A century ago, the difference between the chemistry of living and nonliving matter could be described by "life forces", "vis vitalis", or some special properties peculiar to living matter. - Today, the difference is descr...

# Chapter One: The Rules of the Game ## 1.1 The Makeup of Living Organisms - A century ago, the difference between the chemistry of living and nonliving matter could be described by "life forces", "vis vitalis", or some special properties peculiar to living matter. - Today, the difference is described by the complexity, organization, and sophistication of the reactions. - The chemistry of living things is no different in principle from that of nonliving matter. It is simply more intricate, more subtle, and by the same token more challenging. - The variety of chemical substances present in living organisms is staggering. - The most prevalent substance is water, which may represent as much as 65 percent of the weight of a typical mammal. - The saline composition of this water reflects the origin of the first living things as tiny enclosed bits of seawater, in which especially efficient series of chemical reactions could evolve with time into metabolisms. - Dissolved in this water are a great number of ions and small inorganic and organic molecules: - $K^+$ and $Na^+$ - chlorides and phosphates - organic bases, vitamins - cofactors - If the living organism is thought of as a complex factory, then these small molecules serve as the nuts, bolts, and cogs that keep the wheels of the factory turning, although many of them are present only in very small amounts. - The steel girders of the factory are the inert framework materials: - bones - teeth - the polysaccharide chitin of insects. - Lipids-fats, oils, and their. derivatives-provide part of the lath and plaster of the walls within the factory. - The specifications for everything that goes on in the factory, including the construction of the factory itself, are written down in the nucleic acids: - deoxyribonucleic acid (DNA) - ribonucleic acid (RNA). - But in many respects the most remarkable chemical substances within living organisms are the proteins. ## 1.2 Proteins as Polymers of Amino Acids - A protein is built up from a long-chain polymer of amino acids, called a polyamino acid or polypeptide chain. - Polymers *per se* can be pretty dull. - Polyethylene is good for inert, laboratory beakers and very little else. - Polystyrene and nylon have invaluable but limited properties. - Branched-chain polymers such as polyurethanes, Bakelite resins, and melamac can form three-dimensional networks with widely varying physical properties. - But with all these polymers, the tendency is toward inertness rather than catalytic activity. - Polyaminoacids or polypeptides are more versatile because of the great number of different side chains that may be present. - Each monomer unit has a side chain, which is usually one of the 20 common types. - Some, such as valine, leucine, and isoleucine, are hydrocarbons. - Aspartic and glutamic acid side chains themselves contain an acidic group; lysine, arginine, and histidine are basic. - Some permit cross-linking of chains, either by covalent or hydrogen bonds. - It is the variety of possible side groups that makes proteins so useful. - If there are 61 units in a chain, all alike, then only one chemical substance is possible. - But if each unit has 20 alternatives, the number of possible substances rises to $20^{61}$, or $5 \times 10^{79}$. - This corresponds to approximately six potential structures for every atom in the universe. - With this range of flexibility, the versatility of proteins is easy to understand. - Proteins are linear polymers, often cross-linked but never branched. - The opposite page shows the two most common types of cross-linking: - a covalent disulfide bridge with a bond strength of the order of 50 kilocalories per mole, - a weaker hydrogen bond with about 6 kcal/mole ## 1.3 The Backbone of the Polymer - Many of the special properties of a polypeptide chain arise from the nature of its backbone chain. - Its distinctive feature is the group -CO-NH-, called a peptide bond or amide link. - A polymer with "pseudopeptide" bonds as at the left would have similar overall dimensions, but its chemical behavior would not even remotely resemble that of a protein. - The CO and NH groups are capable of forming cross-links between chains. - The CO and NH groups can overcome the absence of true branching when building up three-dimensional structures. - The peptide bond also severely limits the ways in which the chain can fold: all four atoms in the -CO-NH- group have to lie in the same plane. - Carbon, nitrogen, and oxygen atoms, when they form bonds, ordinarily use their $2s$, $2p$, $2p$, and $2p$ atomic orbitals. - In addition to the two electrons in the filled $1s$ orbital, which play no part in bonding, carbon has four more valence electrons; nitrogen has five; and oxygen has six. - Hydrogen has only one electron, half filling its spherical $1s$ orbital. - In methane, $CH_4$, the four carbon $2s$ and $2p$ orbitals do not combine directly with the hydrogen $1s$, for the hydrogen atoms are observed to be tetrahedrally arranged about the carbon. - The carbon orbitals may be thought of as being combined (hybridized) to form four equivalent $sp^3$ atomic orbitals, directed to the corners of a tetrahedron. - These then each combine with one $1s$ hydrogen orbital to form a molecular orbital that, when filled by two electrons, builds one C-H bond. - The eight valence electrons are thus accounted for in four molecular orbitals. - Because each C-H bond electron cloud is cylindrically symmetrical about the bond axis, these orbitals are referred to as $\sigma$-type molecular orbitals. - The extra stability of the methane molecule over its five isolated atoms can be expressed as that of four C-H bonds with bond energies of 99 kcal/mole each. - The bonding in ethane, $CH_3-CH_3$, is similar. - There are 14 valence electrons, 4 each from the carbons and 1 each from the hydrogens. - There are six $\sigma$-type C-H molecular orbitals and one $\sigma$-type C-C orbital. - Each such orbital is occupied by one pair of valence electrons. - The C-H bond energy is again 99 kcal/mole and that of the C-C bond is 83 kcal. - Ethylene, $CH_2=CH_2$ (shown on the facing page) illustrates the molecular orbital picture of a double bond. - In this molecule, on each carbon atom, the $2s$ and two of the $2p$ orbitals are hybridized to form three equivalent $sp^2$ orbitals, lying $120^\circ$ apart in a plane. - The unused $2p$ orbital has its axis perpendicular to this plane, and its electron cloud is symmetrical above and below the plane. - Four $\sigma$-type C-H bonds are formed, in the usual way, and one $\sigma$-type C-C bond. - These are occupied by 10 of the 12 valence electrons. - But in addition, the two unused $2p$ orbitals also combine to form a different type of C-C molecular orbital. - This orbital is not cylindrically symmetrical about the C-C axis, being made up of two lobes of electron density above and below the plane of the molecule, and reflecting the mirror symmetry of the atomic orbitals from which it arose. - Such an orbital is called a $\pi$-type orbital. - The last two electrons fill this $\pi$ orbital to form the second carbon-carbon bond. - The asymmetry of the orbital requires that all six atoms in the ethylene molecule lie in one plane, for a twist about the C-C bond would forcibly uncouple the two $2p$ orbitals that form it and reduce the double bond to a $\sigma$-type single bond. - The measured bond energy of a carbon-carbon double bond is 147 kcal/mole; that of a single bond is 83 kcal. - Hence an extra 64 kcal/mole would be required to twist one end of the ethylene molecule by $90^\circ$. - So far, the simple molecules we have mentioned can be described by single or double bonds between pairs of atoms - When a carboxyl group is ionized, for example, it might be supposed that one of the carbon-oxygen bonds would remain a carbonyl double bond, $1.23Å$ long, and that the other would remain a single bond, $1.36Å$ long, to the now negatively charged oxygen. - In fact, crystal-structure analyses of salts of carboxylic acids have shown that the two carbon-oxygen bonds are usually equivalent, with an intermediate length of $1.26Å$. - One way of describing this is to say that the true bond structure has the character of a mixture of the two extreme simple bond models, or resonance models. - This terminology is deceptive, for the word "resonance" suggests a flipping back and forth between the two structures, which is wrong. - It is better to say simply that the single bond-double bond picture is too naive and that the real structure has two equivalent bonds which are more than single and less than double. - The negative charge is spread over the entire carboxyl group, and the two bonds each have partial double-bond character. - The electrons that would have been confined to the region of one double bond are said to be "delocalized". - It is generally true that, other things being equal, an electron with more room in which to move around will have a lower energy - Bond structure is more stable than either (a) or (b) by a "resonance stabilization energy" of 28 kcal/mole. ## 1.4 The Influence of Side Chains - If the polypeptide chain provides the fundamental pattern, the ground bass of the composition, it is the side chains that build the melody. - Out of the chemical and x-ray diffraction studies of proteins have gradually come guidelines as to the kinds of amino acid side chains and the parts they play in building a protein. - There are three general categories of side chains: - nonpolar - polar but uncharged - charged polar - On these two pages are shown the 20 common side chains grouped by categories. - The nonpolar residues include those with aliphatic hydrocarbon side chains: - Gly - Ala - Val - Leu - Ilu - Pro - one aromatic group, Phe - one "pseudohydrocarbon," Met - The polar but neutral category contains: - two hydroxyl-containing residues, - Ser - Thr - two amides, - Asn - Gln - two with aromatic rings, - Tyr - Trp - one with a sulfhydryl group, Cys. - In the charged polar class are: - two acidic groups, Asp and Glu - three bases, - His - Lys - Arg - Proteins have evolved for operation in an aqueous environment. - Part of the function of an enzyme is often to provide less polar surroundings for the molecule or molecules on which it acts, its substrate, than are obtainable in solution. - The chemistry of an enzyme-substrate interaction is very much affected by the polarity of the solvent - We shall see in Chapter 4 that the reactivity of lysozyme's own acidic side chains is changed by their local surroundings, and that this is critical in its catalytic activity. - The nonpolar side chains, then, provide the opportunity for a little nonaqueous chemistry. - They also help to hold the molecule together. - When a hydrocarbon chain is in an aqueous medium, it forces the neighboring water molecules to form a cage-like or "clathrate" structure in the immediate vicinity. - This restricts the motion and number of possible arrangements of the water molecules and lowers their entropy. - If these hydrocarbon molecules are segregated in one place instead, then the liberated molecules of water are free to adopt a much less ordered arrangement, and the entropy of the solution rises. - This is why oil droplets separate out spontaneously in water the driving factor is entropy more than it is energy. - Kauzmann (??) has calculated that for every nonpolar, hydrophobic side chain of a protein that is removed from an aqueous to a nonpolar environment, the protein gains an extra 4 kcal of free energy stabilization, chiefly from this entropy effect. - This makes the segregation of hydrophobic side chains a powerful factor in stabilizing a protein molecule in aqueous solution, and leads to the "oil drop" model of a globular protein as a polypeptide chain with all of its nonpolar groups inside and its polar groups outside. - The remainder of the discussion is really concerned with elaborations and exceptions to the "nonpolar in, polar out" rule. - The rule applies with force only to the larger nonpolar groups: - Val - Leu - Ilu - Pro - Phe - Gly and Ala are so small that they apparently can be accommodated on the interior or the surface with equal ease. - Non-polar groups have been found on the surface where they appear to play a role in binding of subunits in complex proteins or of substrates in enzymes. - They do lead to instability, and it is safe to assume that when they are found on the outside, they must be there for a specific purpose. - On the other hand, charged side chains are almost never found away from the surface of the molecule and are much more restricted as to environment. - Most charged groups that are not specifically involved in the function of the protein seem to exist for the sake of interacting with the solvent and keeping that part of the chain in polar surroundings. - The neutral polar residues are usually outside the molecule, but can be inside if their polar groups are "neutralized" by hydrogen bonding to other like residues or to the carbonyl C=O group of the main chain. - Ser, Thr, Asn, and Gln are often used to cross-link two chains by means of hydrogen bonds. - Tyr and Trp have been found inside and outside, but when Tyr is inside, its hydroxyl group is always hydrogen-bonded. - The "charged polar" groups, acidic or basic, can exist in either uncharged or charged form, depending on the pH of the surroundings. - Under acid conditions, Asp and Glu have an uncharged carboxyl group, whereas His, Lys, and Arg each are protonated and carry a positive charge. - Under basic conditions, the carboxyl groups of Asp and Glu will be ionized, and His, Lys, and Arg will be uncharged. - The actual ratio of the acidic to the basic form of a given residue depends on its strength as an acid or base. - The pH at which the two forms are present in equal amounts is called the pK. - Moving one or two pH units away from the pK in either direction causes the ratio of the two forms to change to 10:1 or 100:1, respectively. - Asp and Glu have pK values of 3.86 and 4.25, respectively. - His is 6.00, Lys is 10.53, and Arg is 12.48. - Under normal physiological conditions, near pH 7, Asp and Glu will be almost entirely in their basic, or charged, form. - Lys and Arg will be in their acid form, positively charged, but His will be largely uncharged. - It will be about 10 percent protonated and is capable of playing a dual role. - The Tyr hydroxyl group is weakly acidic with a pK of 10.07. - Only about 0.1 percent will be ionized at pH 7, and hence Tyr has been classed as an uncharged polar group. - The forms shown on page 16 are those most prevalent at pH 7. ## Appendix: 1.4 The Influence of Side Chains (cont.) - The amino acids are categorized based on their side chains, which influence their properties. - **Polar residues** are charged or uncharged, making them hydrophilic and able to interact with aqueous solutions. - **Acidic residues** are negatively charged, often on the surface of the molecule, enabling interactions with the solvent. - **Basic residues** are positively charged, often on the surface of the molecule, enabling interactions with the solvent. - **Neutral residues** have uncharged polar side chains, often hydrogen bonding to other residues to maintain them in their position. - **Nonpolar residues** have hydrophobic side chains, typically found in the interior of the molecule, driving the formation of a more stable, nonpolar environment away from an aqueous solution.

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