PROTEIN STRUCTURE (51-100) PDF

The Fischer Convention Describes the Configuration of Asymmetric Centers. Biochemists commonly use the Fischer convention to describe different forms of chiral molecules. In this system, the configuration of the groups around an asymmetric center is compared to that of glyceraldehyde, a molecule wit...

The Fischer Convention Describes the Configuration of Asymmetric Centers. Biochemists commonly use the Fischer convention to describe different forms of chiral molecules. In this system, the configuration of the groups around an asymmetric center is compared to that of glyceraldehyde, a molecule with one asymmetric center. In 1891, Emil Fischer proposed that the spatial isomers, or stereoisomers, of glyceraldehyde be designated Dglyceraldehyde and L-glyceraldehyde (Fig. ). The prefi x L (note the use of a small upper-case letter) signified rotation of polarized light to the left (Greek: levo, left), and the prefi x D indicated rotation to the right (Greek: dextro, right) by the two forms of glyceraldehyde. Fischer assigned the prefi xes to the structures shown in Fig. without knowing whether the structure on the left and the structure on the right were actually levorotatory or dextrorotatory, respectively. Only in 1949 did experiments confirm that Fischer’s guess was indeed correct. Fischer also proposed a shorthand rotation for molecular confi gurations, known as Fischer projections, which are also given in Fig. In the Fischer convention, horizontal bonds extend above the plane of the paper and vertical bonds extend below the plane of the paper. The confi guration of groups around any chiral center can be related to that of glyceraldehyde by chemically converting the groups to those of glyceraldehyde. For α-amino acids, the amino, carboxyl, R, and H groups around the Cα atom correspond to the hydroxyl, aldehyde, CH2OH, and H groups, respectively, of glyceraldehyde. Configuration may also result from the presence of asymmetric carbons. Therefore, L-glyceraldehyde and L-α-amino acids are said to have the same relative confi guration. All amino acids derived from proteins have the L stereochemical configuration; that is, they all have the same relative confi guration around their Cα atoms. Of course, the L or D designation of an amino acid does not indicate its ability to rotate the plane of polarized light. Many Lamino acids are dextrorotatory. The Fischer system has some shortcomings, particularly for molecules with multiple asymmetric centers. Each asymmetric center can have two possible confi gurations, so a molecule with n chiral centers has 2n diff erent possible stereoisomers. Threonine and isoleucine, for example, each have two chiral carbon atoms, and therefore each has four stereoisomers, or two pairs of enantiomers. [The enantiomers (mirror images) of the L forms are the D forms.] For most purposes, the Fischer system provides an adequate description of biological molecules. A more precise nomenclature system is also occasionally used by biochemists. Life Is Based on Chiral Molecules. Consider the ordinary chemical synthesis of a chiral molecule, which produces a racemic mixture (containing equal amounts of each enantiomer). To obtain a product with net asymmetry, a chiral process must be employed. One of the most striking characteristics of life is its production of optically active molecules. Biosynthetic processes almost invariably produce pure stereoisomers. The fact that the amino acid residues of proteins all have the L confi guration is just one example of this phenomenon. Furthermore, because most biological molecules are chiral, a given molecule— present in a single enantiomeric form—will bind to or react with only a single enantiomer of another compound. For example, a protein made of L-amino acid residues that reacts with a particular L-amino acid does not readily react with the D form of that amino acid. An otherwise identical synthetic protein made of D-amino acid residues, however, readily reacts only with the corresponding D-amino acid. D-Amino acid residues are components of some relatively short ( OH > NH2 > COOH > CHO > CH2OH > C6H5 > CH3 > H The prioritized groups are assigned the letters W, X, Y, Z such that their order of priority ranking is W > X > Y > Z. To establish the confi guration of the chiral center, it is viewed from the asymmetric center toward the Z group (lowest priority). If the order of the groups W → X → Y is clockwise, the confi guration is designated R (Latin: rectus, right). If the order of W → X → Y is counterclockwise, the confi guration is designated S (Latin: sinistrus, left). L-Glyceraldehyde is (S)-glyceraldehyde because the three highest priority groups are arranged counterclockwise when the H atom is positioned behind the chiral C atom. All the L-amino acids in proteins are (S)-amino acids except cysteine, which is (R)-cysteine because the S in its side chain increases its priority. Other closely related compounds with the same designation under the Fischer DL convention may have different representations under the RS system. The RS system is particularly useful for describing the chiralities of compounds with multiple asymmetric centers. Thus, L-threonine can also be called (2S,3R)-threonine. Amino Acid Derivatives KEY CONCEPTS The side chains of amino acid residues in proteins may be covalently modified. Some amino acids and amino acid derivatives function as hormones and regulatory molecules. The 20 common amino acids are by no means the only amino acids that occur in biological systems. “Nonstandard” amino acid residues are often important constituents of proteins and biologically active peptides. In addition, many amino acids are not constituents of polypeptides at all but independently play a variety of biological roles. Protein Side Chains May Be Modified The “universal” genetic code, which is nearly identical in all known life-forms , specifies only the 20 standard amino acids. Nevertheless, many other amino acids, are components of certain proteins. In almost all cases, these unusual amino acids result from the specific modification of an amino acid residue after the polypeptide chain has been synthesized. Amino acid modifications include the simple addition of small chemical groups to certain amino acid side chains: hydroxylation, methylation, acetylation, carboxylation, and phosphorylation. Larger groups, including lipids and carbohydrate polymers, are attached to particular amino acid residues of certain proteins. The free amino and carboxyl groups at the N- and C-termini of a polypeptide can also be chemically modified. These modifications are often important, if not essential, for the function of the protein. In some cases, several amino acid side chains together form a novel structure. Perspectives in Biochemistry Green Fluorescent Protein Genetic engineers often link a protein-coding gene to a “reporter gene”—for example, the gene for an enzyme that yields a colored reaction product. The intensity of the colored compound can be used to estimate the level of expression of the engineered gene. One of the most useful reporter genes is the one that codes for green fluorescent protein (GFP). This protein, from the bioluminescent jellyfi sh Aequorea victoria, fluoresces with a peak wavelength of 508 nm (green light) when irradiated by ultraviolet or blue light (optimally 400 nm). Green fluorescent protein is nontoxic and intrinsically fluorescent; it requires no substrate or small molecule cofactor to fluoresce, as do other highly fluorescent proteins. Consequently, when the gene for green fluorescent protein is linked to another gene, the level of expression of the fused genes can be measured noninvasively by fluorescence microscopy. Green fl uorescent protein consists of a chain of 238 amino acid residues. The light-emitting group is a derivative of three consecutive amino acids:Ser, Tyr, and Gly. After the protein has been synthesized, the three amino acids undergo spontaneous cyclization and oxidation. The carbonyl C atom of Ser forms a covalent bond to the amino N atom contributed by Gly, followed by the elimination of water and the oxidation of the Cα—Cβ bond of Tyr to a double bond. The resulting structure contains a system of conjugated double bonds that gives the protein its fluorescent properties. Cyclization between Ser and Gly is probably rapid, and the oxidation of the Tyr side chain (by O2) is probably the rate-limiting step of fluorophore generation. Genetic engineering has introduced site-specific mutations that enhance fluorescence intensity and shift the wavelength of the emitted light to different colors, thereby making it possible to simultaneously monitor the expression of two or more different genes. Some Amino Acids Are Biologically Active The 20 standard amino acids undergo a bewildering number of chemical transformations to other amino acids and related compounds as part of their normal cellular synthesis and degradation. In a few cases, the intermediates of amino acid metabolism have functions beyond their immediate use as precursors or degradation products of the 20 standard amino acids. Moreover, many amino acids are synthesized not to be residues of polypeptides but to function independently. We will see that many organisms use certain amino acids to transport nitrogen in the form of amino groups. Amino acids may also be oxidized as metabolic fuels to provide energy. In addition, amino acids and their derivatives often function as chemical messengers for communication between cells. For example, glycine, !-aminobutyric acid(GABA; a glutamate decarboxylation product), and dopamine (a tyrosine derivative) are neurotransmitters, substances released by nerve cells to alter the behavior of their neighbors. Histamine (the decarboxylation product of histidine) is a potent local mediator of allergic reactions. Thyroxine (another tyrosinederivative) is an iodine containing thyroid hormone that generally stimulates vertebrate metabolism. Many peptides containing only a few amino acid residues have important physiological functions as hormones or other regulatory molecules. One nearly ubiquitous tripeptide called glutathione plays a role in cellular metabolism. Glutathione is a Glu–Cys–Gly peptide in which the γ-carboxylate group of the glutamate side chain forms an isopeptide bond with the amino group of the Cys residue (so called because a standard peptide bond is taken to be the amide bond formed between an α-carboxylate and an α-amino group of two amino acids). Two of these tripeptides (abbreviated GSH) undergo oxidation of their SH groups to form a dimeric disulfide-linked structure called glutathione disulfide Glutathione helps inactivate oxidative compounds that could potentially damage cellular structures, since the oxidation of GSH to GSSG is accompanied by the reduction of another compound (shown as O2 above): 2 GSH + Xoxidized→GSSG + Xreduced GSH must then be regenerated in a separate reduction reaction. Summary 1.Amino Acid Structure At neutral pH, the amino group of an amino acid is protonated and its carboxylic acid group is ionized. Proteins are polymers of amino acids joined by peptide bonds. The 20 standard amino acids can be classified as nonpolar (Gly, Ala,Val, Leu, Ile, Met, Pro, Phe, Trp), uncharged polar (Ser, Thr, Asn, Gln, Tyr, Cys), and charged (Lys, Arg, His, Asp, Glu). The pK values of the ionizable groups of amino acids may be altered when the amino acid is part of a polypeptide. 2 Stereochemistry Amino acids are chiral molecules. Only L-amino acids occur in proteins (some bacterial peptides contain D-amino acids). 3 Amino Acid Derivatives Amino acids may be covalently modifi ed after they have been incorporated into a polypeptide. Individual amino acids and their derivatives have diverse physiological functions. References Barrett, G.C. and Elmore, D.T., Amino Acids and Peptides, Cambridge University Press (2001). [Includes structures of the common amino acids along with a discussion of their chemical reactivities and information on analytical properties.] Lamzin, V.S., Dauter, Z., and Wilson, K.S., How nature deals with stereoisomers, Curr. Opin. Struct. Biol. 5, 830–836 (1995). [Discusses proteins synthesized from D-amino acids.] Solomons, G.T.W., Fryhle, C., and Snyder, S.A., Organic Chemistry (11th ed.), Chapter 5, Wiley (2014). [A discussion of chirality. Most other organic chemistry textbooks contain similar material.] Paleobiologists use techniques such as mass spectrometry to analyze the proteins in ancient animal bones to identify the species—such as sheep or goat—and draw conclusions about early human farming practices. Unlike PCR, mass spectrometry does not require intact macromolecules for analysis and is not as sensitive to contamination. Protein Structure Proteins are at the center of action in biological processes. Nearly all the molecular transformations that define cellular metabolism are mediated by protein catalysts. Proteins also perform regulatory roles, monitoring extracellular and intracellular conditions and relaying information to other cellular components. In addition, proteins are essential structural components of cells. A complete list of known protein functions would contain many thousands of entries, including proteins that transport other molecules and proteins that generate mechanical and electrochemical forces, and such a list would not account for the thousands of proteins whose functions are not yet fully characterized or, in many cases, are completely unknown. One of the keys to deciphering the function of a given protein is to understand. Like the other major biological macromolecules, the nucleic acids , and the polysaccharides , proteins are polymers of smaller units. But unlike many nucleic acids, proteins do not have uniform, regular structures. This is, in part, because the 20 kinds of amino acid residues from which proteins are made have widely differing chemical and physical properties. The sequence in which these amino acids are strung together can be analyzed directly, or indirectly, via DNA sequencing. In either case, amino acid sequence information provides insights into the chemical and physical properties of proteins, their relationships to other proteins, and, ultimately, their mechanisms of action in living organisms. Polypeptide Diversity KEY CONCEPTS In theory, the sizes and compositions of polypeptide chains are unlimited. In cells, this potential variety is limited by the efficiency of protein synthesis and by the ability of the polypeptide to fold into a functional structure. Primary Assembly Secondary Folding Tertiary Packing Quaternary Interaction PROCESS STRUCTURE Protein Structure Like all polymeric molecules, proteins can be described in terms of levels of organization; in this case, their primary, secondary, tertiary, and quaternary structures. A protein’s primary structure is the amino acid sequence of its polypeptide chain, or chains if the protein consists of more than one polypeptide. Higher levels of protein structure— secondary, tertiary, and quaternary—refer to the three-dimensional shapes of folded polypeptide chains and will be described in the next chapter. Proteins are synthesized in vivo by the stepwise polymerization of amino acids in the order specified by the sequence of nucleotides in a gene. The direct correspondence between one linear polymer (DNA) and another (a polypeptide) illustrates the elegant simplicity of living systems and allows us to extract information from one polymer and apply it to the other. Protein Assembly occurs at the ribosome involves polymerization of amino acids attached to tRNA yields primary structure Primary Structure primary structure of human insulin CHAIN 1: GIVEQ CCTSI CSLYQ LENYC N CHAIN 2: FVNQH LCGSH LVEAL YLVCG ERGFF YTPKT linear ordered 1 dimensional sequence of amino acid polymer by convention, written from amino end to carboxyl end a perfectly linear amino acid polymer is neither functional nor energetically favorable à folding! The Theoretical Possibilities for Polypeptides Are Unlimited. With 20 different choices available for each amino acid residue in a polypeptide chain, it is easy to see that a huge number of different protein molecules are possible. For a protein of n residues, there are 20n possible sequences. A relatively small protein molecule may consist of a single polypeptide chain of 100 residues. There are 20100 ≈ 1.27 × 10130 possible unique polypeptide chains of this length, a quantity vastly greater than the estimated number of atoms in the universe (9 × 1078). Clearly, evolution has produced only a tiny fraction of the theoretical possibilities—a fraction that nevertheless represents an astronomical number of different polypeptides. 20^100 ~= 1.27 x 10 ^130 possible unique polypeptide chains greater than the estimated number of atoms in the universe (9 x 10^78) Actual Polypeptides Are Somewhat Limited in Size and Composition. In general, proteins contain at least 40 residues or so; polypeptides smaller than that are simply called peptides. The largest known polypeptide chain belongs to the 35,213-residue titin, a giant (3906 kD) protein that helps arrange the repeating structures of muscle fibers. However, the vast majority of polypeptides contain between 100 and 1000 residues. Multisubunit proteins contain several identical and/or nonidentical chains called subunits. Some proteins are synthesized as single polypeptides that are later cleaved into two or more chains that remain associated; insulin is such a protein. The size range in which most polypeptides fall probably reflects the optimization of several biochemical processes: 1. Forty residues appears to be near the minimum for a polypeptide chain to fold into a discrete and stable shape that allows it to carry out a particular function. 2. Polypeptides with well over 1000 residues may approach the limits of efficiency of the protein synthetic machinery. The longer the polypeptide(and the longer its corresponding mRNA), the greater the likelihood of introducing errors during transcription and translation. The amino acid compositions of proteins differ between proteins and are highly variable. Some amino acids occur only once or not at all in a given protein and other amino acids may occur in large numbers.Based on the frequencies at which the 20 standard amino acids occur in proteins, and their molecular weights , the average molecular weight of an amino acid in a protein is 128. Because a molecule of water (Mr 18) is lost on creation of each peptide bond, the average molecular weight of an amino acid residue in a protein is about 110. In addition to these mild constraints on size, polypeptides are subject to more severe limitations on amino acid composition. The 20 standard amino acids do not appear with equal frequencies in proteins. (Table 3-3 lists the average occurrence of each amino acid residue.) For example, the most abundant amino acids in proteins are Leu, Ala, Gly, Val, Glu, and Ser; the rarest are Trp, Cys, Met, and His. Because each amino acid residue has characteristic chemical and physical properties, its presence at a particular position in a protein influences the properties of that protein. In particular, as we will see, the three-dimensional shape of a folded polypeptide chain is a consequence of the intramolecular forces among its various residues. In general, a protein’s hydrophobic residues cluster in its interior, out of contact with water, whereas its hydrophilic side chains tend to occupy the protein’s surface. The characteristics of an individual protein depend more on its amino acid sequence than on its amino acid composition per se, for the same reason that “kitchen” and its anagram “thicken” are quite different words. In addition, many proteins consist of more than just amino acid residues. They may form complexes with metal ions such as Zn2+ and Ca2+; they may covalently or noncovalently bind certain small organic molecules; and they may be covalently modifi ed by the posttranslational attachment of groups such as phosphates and carbohydrates. Conjugated Proteins Simple proteins, such as chymotrypsin, contain only amino acids. Other proteins--conjugated proteins--contain other associated chemical components in addition to amino acids. The non-amino acid part of a conjugated protein is called its prosthetic group. Examples of conjugated proteins and their prosthetic groups are listed in Table 3-4. The blue plumage of this penguin, Eudyptula minor, is not due to the presence of blue pigment molecules but results from the light scattered by parallel bundles of the protein beta keratin. For many years, it was thought that proteins were colloids of random structure and that the enzymatic activities of certain crystallized proteins were due to unknown entities associated with an inert protein carrier. In 1934, J.D. Bernal and Dorothy Crowfoot Hodgkin showed that a crystal of the protein pepsin yielded a discrete diffraction pattern when placed in an X-ray beam. This result provided convincing evidence that pepsin was not a random colloid, but an ordered array of atoms organized into a large yet uniquely structured molecule. Even relatively small proteins contain thousands of atoms, almost all of which occupy definite positions in space. The fi rst X-ray structure of a protein, that of sperm whale myoglobin, was reported in 1958 by John Kendrew and coworkers. At the time—only 5 years after James Watson and Francis Crick had elucidated the simple and elegant structure of DNA —protein chemists were chagrined by the complexity and apparent lack of regularity in the structure of myoglobin. In retrospect, such irregularity seems essential for proteins to fulfi ll their diverse biological roles. However, comparisons of the ∼110,000 protein structures now known have revealed that proteins actually exhibit a remarkable degree of structural regularity. As we saw the primary structure of a protein is its linear sequence of amino acids. In discussing protein structure, three further levels of structural complexity are customarily invoked: Secondary structure is the local spatial arrangement of a polypeptide’s backbone atoms without regard to the conformations of its side chains. Tertiary structure refers to the three-dimensional structure of an entire polypeptide, including its side chains. Many proteins are composed of two or more polypeptide chains, loosely referred to as subunits. A protein’s quaternary structure refers to the spatial arrangement of its subunits Secondary Structure KEY CONCEPTS The planar character of the peptide group limits the conformational flexibility of the polypeptide chain. The α helix and the β sheet allow the polypeptide chain to adopt favorable ϕ and ψ angles and to form hydrogen bonds. Fibrous proteins contain long stretches of regular secondary structure, such as the coiled coils in α keratin and the triple helix in collagen. Not all polypeptide segments form regular secondary structures such as α helices or β sheets. Protein secondary structure includes the regular polypeptide folding patterns such as helices, sheets, and turns. However, before we discuss these basic structural elements, we must consider the geometric properties of peptide groups, which underlie all higher order structures. The Planar Peptide Group Limits Polypeptide Conformations A polypeptide is a polymer of amino acid residues linked by amide (peptide) bonds. In the 1930s and 1940s, Linus Pauling and Robert Corey determined the X-ray structures of several amino acids and dipeptides in an effort to elucidate the conformational constraints on a polypeptide chain. These studies indicated that the peptide group has a rigid, planar structure as a consequence of resonance interactions that give the peptide bond ∼40% double-bond character Ramachandran Plot Pauling built models based on the following principles, codified by Ramachandran: (1) bond lengths and angles – should be similar to those found in individual amino acids and small peptides (2) peptide bond – should be planer (3) overlaps – not permitted, pairs of atoms no closer than sum of their covalent radii (4) stabilization – have sterics that permit hydrogen bonding Two degrees of freedom: (1) f (phi) angle = rotation about N – Ca (2) y (psi) angle = rotation about Ca – C A linear amino acid polymer with some folds is better but still not functional nor completely energetically favorable à packing! Protein Folding occurs in the cytosol yields secondary structure involves localized spatial interaction among primary structure elements, i.e. the amino acids The Most Common Regular Secondary Structures Are the " Helix and the # Sheet A few elements of protein secondary structure are so widespread that they are immediately recognizable in proteins with widely differing amino acid sequences. Both the " helix and the # sheet are such elements; they are called regular secondary structures because they are composed of sequences of residues with repeating ϕ and ψ values. The " Helix Has a Regularly Repeating Structure. Only one polypeptide helix has both a favorable hydrogen bonding pattern and ϕ and ψ values that fall within the fully allowed regions of the Ramachandran diagram: the α helix. Its discovery by Linus Pauling in 1951, through model building, ranks as one of the landmarks of structural biochemistry Linus Pauling and Structural Biochemistry Linus Pauling (1901–1994) Linus Pauling, the only person to have been awarded two unshared Nobel prizes, is clearly the dominant figure in twentieth-century chemistry and one of the greatest scientific figures of all time. He received his B.Sc. in chemical engineering from Oregon Agricultural College (now Oregon State University) in 1922 and his Ph.D. in chemistry from the California Institute of Technology in 1925, where he spent most of his career. The major theme throughout Pauling’s long scientific life was the study of molecular structures and the nature of the chemical bond. He began this career by using the then recently invented technique of X-ray crystallography to determine the structures of simple minerals and inorganic salts. At that time, methods for solving the phase problem were unknown, so X-ray structures could be determined only using trial-and-error techniques. This limited the possible molecules that could be effectively studied to those with few atoms and high symmetry such that their atomic coordinates could be fully described by only a few parameters (rather than the threedimensional coordinates of each of its atoms). Pauling realized that the positions of atoms in molecules were governed by fixed atomic radii, bond distances, and bond angles and used this information to make educated guesses about molecular structures. This greatly extended the complexity of the molecules whose structures could be determined. In his next major contribution, occurring in 1931, Pauling revolutionized the way that chemists viewed molecules by applying the then infant fi eld of quantum mechanics to chemistry. Pauling formulated the theories of orbital hybridization, electron-pair bonding, and resonance and thereby explained the nature of covalent bonds. This work was summarized in his highly infl uential monograph, The Nature of the Chemical Bond, which was first published in 1938. In the mid-1930s, Pauling turned his attention to biological chemistry. He began these studies in collaboration with his colleague, Robert Corey, by determining the X-ray structures of several amino acids and dipeptides. At that time, the X-ray structural determination of even such small molecules required around a year of intense effort, largely because the numerous calculations required to solve a structure had to be made by hand (electronic computers had yet to be invented). Nevertheless, these studies led Pauling and Corey to the conclusions that the peptide bond is planar, which Pauling explained from resonance considerations, and that hydrogen bonding plays a central role in maintaining macromolecular structures. In the 1940s, Pauling made several unsuccessful attempts to determine whether polypeptides have any preferred conformations. Then, in 1948, while visiting Oxford University, he was confined to bed by a cold. He eventually tired of reading detective stories and science fiction and again turned his attention to proteins By folding drawings of polypeptides in various ways, he discovered the α helix, whose existence was rapidly confirmed by X-ray studies of α keratin. This work was reported in 1951, and later that year Pauling and Corey also proposed both the parallel and antiparallel β pleated sheets. For these groundbreaking insights, Pauling received the Nobel Prize in Chemistry in 1954, although α helices and β sheets were not actually visualized until the first X-ray structures of proteins were determined, five to ten years later. Pauling made numerous additional pioneering contributions to biological chemistry, most notably that the heme group in hemoglobin changes its electronic state on binding oxygen , that vertebrate hemoglobins are α2β2 heterotetramers that the denaturation of proteins is caused by the unfolding of their polypeptide chains, that sickle-cell anemia is caused by a mutation in the β chain of normal adult hemoglobin (the first so-called molecular disease to be characterized; , that molecular complementarity plays an important role in antibody–antigen interactions and, by extension, all macromolecular interactions, that enzymes catalyze reactions by preferentially binding their transition states , and that the comparison of the sequences of the corresponding proteins in different organisms yields evolutionary insights. Pauling was also a lively and stimulating lecturer who for many years taught a general chemistry course [which one of the authors of this textbook (DV) had the privilege of taking]. His textbook, General Chemistry, revolutionized the way that introductory chemistry was taught by presenting it as a subject that could be understood in terms of atomic physics and molecular structure. For a book of such generality, an astounding portion of its subject matter had been elucidated by its author. Pauling’s amazing grasp of chemistry was demonstrated by the fact that he dictated each chapter of the textbook in a single sitting. By the late 1940s, Pauling became convinced that the possibility of nuclear war posed an enormous danger to humanity and calculated that the radioactive fallout from each aboveground test of a nuclear bomb would ultimately cause cancer in thousands of people. He therefore began a campaign to educate the public about the hazards of bomb testing and nuclear war. The political climate in the United States at the time was such that the government considered Pauling to be subversive and his passport was revoked (and returned only two weeks before he was to leave for Sweden to receive his first Nobel prize). Nevertheless, Pauling persisted in this campaign, which culminated, in 1962, with the signing of the first nuclear test ban treaty. For his efforts, Pauling was awarded the 1962 Nobel Peace Prize. Pauling saw science as the search for the truth, which included politics and social causes. In his later years, he became a vociferous promoter of what he called orthomolecular medicine, the notion that large doses of vitamins could ward off and cure many human diseases, including cancer. In the best known manifestation of this concept, Pauling advocated taking large doses of vitamin C to prevent the common cold and lessen its symptoms, advice still followed by millions of people, although the medical evidence supporting this notion is scant. It should be noted, however, that Pauling, who followed his own advice, remained active until he died in 1994 at the age of 93. Secondary Structure non-linear 3 dimensional localized to regions of an amino acid chain formed and stabilized by hydrogen bonding, electrostatic and van der Waals interactions The α helix (Fig.) is right-handed; that is, it turns in the direction that the fingers of a right hand curl when its thumb points in the direction that the helix rises. The α helix, which ideally has ϕ = −57° and ψ = −47°, has 3.6 residues per turn and a pitch (the distance the helix rises along its axis per turn) of 5.4 A. The α helices of proteins have an average length of ∼12 residues, which corresponds to more than three helical turns, and a length of ∼18 A. In the α helix, the backbone hydrogen bonds are arranged such that the peptide C O bond of the nth residue points along the helix axis toward the peptide N H group of the (n + 4)th residue. This results in a strong hydrogen bond that has the nearly optimum N…O distance of 2.8 A. Amino acid side chains project outward and downward from the helix , thereby avoiding steric interference with the polypeptide backbone and with each other. The core of the helix is tightly packed; that is, its atoms are in van der Waals contact. Space-filling model of an ! helix. The backbone atoms are colored according to type with C green, N blue, O red, and H white. The side chains (gold) project away from the helix. This α helix is a segment of sperm whale myoglobin. [Based on an X-ray structure by Ilme Schlichting, Max Planck Institut für Molekulare Physiologie, Dortmund, Germany. Secondary Structure non-linear 3 dimensional localized to regions of an amino acid chain formed and stabilized by hydrogen bonding, electrostatic and van der Waals interactions