PAULING, Linus & COREY, Robert B.

The structure of proteins: two hydrogen-bonded helical configurations of the polypeptide chain (co-author H. R. BRANSON); Atomic coordinates and structure factors for two helical configurations of polypeptide chains; The structure of synthetic polypeptides; The pleated sheet, a new layer configuration of polypeptide chains; The structure of feather rachis keratin; The structure of hair, muscle, and related proteins; The structure of fibrous proteins of the collagen-gelatin group; The polypeptide-chain configuration in hemoglobin and other globular proteins. Eight papers in a single offprint from: Proceedings of the National Academy of Sciences, Vol. 27, Nos, 4, 5, April, May 1951. [With:] Fundamental dimensions of polypeptide chains; Stable configurations of polypeptide chains. Two papers in a single offprint from: Proceedings of the Royal Society B, Vol. 141, No. 1, March 1953.

[London: Cambridge University Press for the Royal Society, 1951-53].

First edition, very rare offprints, signed by Pauling. “In April of 1951, readers who turned the pages of PNAS were treated to a surprise: seven studies from the same authors, published back-to-back, all on the subject of protein structure … Grouping the papers together for maximum attention, authors Linus Pauling and Robert Corey must have realized the bombshell they had dropped on the scientific world. Knowledge of the inner workings of proteins — molecules often referred to as the building blocks of life — would be the key to understanding biology at the molecular level” (Christen Brownlee, The Protein Papers, 2012). “Protein research was one of the major areas of study in x-ray crystallography and biochemistry, with British x-ray crystallographers such as John Desmond Bernal, Dorothy Hodgkin, and William Astbury among the pioneers in the field. While visiting Oxford in 1948 and confined with the flu, Pauling started building protein models, constructing a three-dimensional model of keratin as a spiral molecular structure using paper, ruler, and pencil to sketch out a chain of amino acids, and drawing the atomic-bond lengths and angles from memory. He realized, however, that an x-ray pattern produced from his model would not match the x-ray patterns that Astbury had published. After his return to Caltech, Pauling set to work with Herman Branson and Robert Corey to come up with an accurate model. In 1950 he and Corey published two structures for keratin, using hydrogen bonding for a coiled peptide chain. Their α-helix model had 3.7 amino acid residues per turn and called for a diffraction pattern showing about 5.4 angstroms between each turn, not quite on target with Astbury’s value of 5.1 angstroms. The fiber manufacturing firm of Courtaulds in London soon confirmed the α-helix in its commercial synthesis of artificial fiber similar to natural keratin, as did Perutz in later studies of natural keratin in the form of horsehair. In May 1951 Pauling and his coworkers published seven papers on protein structures in one issue of the Proceedings of the National Academy of Sciences (PNAS), including the α-helix, parallel and antiparallel pleated sheets, and a winding three-helix model for the protein collagen” (DSB). “A decade before the structures of entire proteins were first revealed by x-ray crystallography, Linus Pauling and Robert Corey of the California Institute of Technology deduced the two main structural features of proteins: the α-helix and β-sheet, now known to form the backbones of tens of thousands of proteins. Their deductions, triumphs in building models of large molecules based on features of smaller molecules, were published in a series of eight articles, communicated to PNAS in February and March 1951. Their work had a significance for proteins comparable to that 2 years later of the Watson–Crick paper for DNA, which adopted the Pauling–Corey model-building approach” (Eisenberg). “New Scientist magazine once characterized Pauling as one of ‘the 20 greatest scientists of all time, on a par with Newton, Darwin, and Einstein.’ Pauling has also been called one of the two greatest scientists of the 20th century (the other being Einstein) and the greatest chemist since Antoine-Laurent Lavoisier, the 18th-century founder of modern chemistry” (American Chemical Society). Pauling is the only person in history to win two unshared Nobel Prizes – the 1954 chemistry prize “for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances”, and the Nobel Peace Prize in 1962. This offprint was issued first in brown printed wrappers and somewhat later, presumably because the supply of these was exhausted, in cheaper white printed wrappers as here. The text is identical in both.

“As Pauling was learning more and more about the structures of relatively simple molecules, in the mid-1930s, it occurred to him that he might as well make an attempt to learn about larger systems. He was aware of the importance of biopolymers and that the understanding of their structures might be a step toward understanding biological processes. Proteins were an obvious choice, because they were the most important biopolymers. At that time nucleic acids were already known, and their building blocks, the nucleotides, had been identified, but the nucleic acids were not considered to be of great significance. There was a hypothesis by Phoebus Levene about the tetranucleotide structure that was based on an erroneous observation that the four nucleotides in nucleic acid were present in equal amounts. Hence, the nucleic acids were thought to be dull, uninteresting molecules, not capable of carrying any great amount of information.

“When Pauling started thinking about protein structures, the first protein to attract his attention was hemoglobin, which is the vehicle of carrying oxygen in our organism. Incidentally, the British group engaged in protein structure studies had also selected hemoglobin for their target; their choice was independent of Pauling’s interest. At the end of the 1920s, Gilbert Adair in Cambridge, UK, showed that the hemoglobin molecule consists of four units each with an iron atom, and each iron could bind an oxygen atom. Pauling formulated a theory about the oxygen uptake of hemoglobin and the structural features of this molecule related to its function of disposing of and taking up oxygen.

“His interest in protein structures was further whetted when a visiting scientist and protein specialist, Alfred Mirsky of the Rockefeller Institute, spent the academic year 1935–1936 in his laboratory. They jointly studied the phenomenon of denaturation of proteins by heat or chemical substances and formulated a theory about it. In this theory, they described the native protein as having a regularly folded structure in which hydrogen bonds provided the stability of the structure. Hydrogen bonding was a recently discovered phenomenon; it was becoming recognized as a crucial mode of interaction in chemical structures and especially in those of biological importance. In retrospect, it was a pivotal discovery, but its significance emerged only gradually over the years. For many biological molecules it is the hydrogen bonds that keep their different parts together.

“Pauling postulated that the subsequent amino acid units are linked to each other in the folded protein molecule not only by the normal peptide bond but also by hydrogen bonding that is facilitated by the folding of the protein, which brings the participating atoms sufficiently close to each other for such interactions. In Pauling’s and Mirsky’s conclusion, when the protein molecule is denatured it undergoes complete or partial unfolding accompanied by breaking the hydrogen bonds. This was a hypothesis, because they knew practically nothing about the nature of folding; finding more about it occupied Pauling’s mind for the next 15 years.

“By the time Pauling became engaged in this research it had been established from rudimentary X-ray diffraction patterns that there might be two principal types of protein structure. Keratin fibers, such as hair, horn, porcupine quill, and fingernail belonged to one, and silk to the other. The foremost British crystallographer of fibers, William T. Astbury showed in the early 1930s that the diffraction pattern of hair underwent changes when it was stretched. He called the one producing the normal pattern alpha keratin and the other, which was similar to the pattern from silk, beta keratin. In 1937, Pauling set out to determine the structure of alpha keratin. He did not just want to rely on a single source of information. He planned to use all his accumulated knowledge in structural chemistry and find the best model that would make sense on this background and would be compatible with the X-ray diffraction pattern.

“There was one piece of information from X-ray diffraction that seemed to be a good point of reference and that was the structural unit—whatever it would be—along the axis of the protein molecules repeated at the distance of 5.1 angstrom. He also knew the dimensions of the peptide group, that is, the characteristic sizes of the group linking the amino acids to each other in the protein chain. The C–N bond in the peptide linkage was not simply a single bond, but it was not a purely double bond either. Pauling’s involvement with the resonance theory taught him that the emerging structure could be represented by two resonating structures.

“Hence, the resonance theory suggested that the C–N bond in the peptide linkage had a partial double bond character. From the accumulated structural information he also knew that the bonds around a double bond are all in the same plane. This was a very important piece of information because rather than taking into account all kinds of rotational forms with respect to the peptide bond, he could assume that it was a planar configuration. This assumption greatly reduced the number of possible models he had to consider for describing the structure of alpha keratin. Nonetheless, at this time Pauling was unable to find a model that would fit the X-ray diffraction pattern and he postponed further study on protein structures.

“During the ensuing years Pauling and his newly arrived associate, Robert Corey, an expert in X-ray crystallography, carried out a large amount of experimental work determining the structures of individual amino acids and simple peptides. At some time every doctoral student in Pauling’s laboratory was supposed to determine the structure of an amino acid for his PhD dissertation. The study was interrupted by World War II but continued vigorously upon its conclusion. Pauling returned to the question of the structure of alpha keratin in 1948 while he was a visiting professor at Oxford University in England.

“Not only had the amount of experimental information in the meantime expanded considerably, but Pauling could take a more detached view of the problem in his renewed efforts. When he was looking for the solution more than a decade before, he was bothered by the knowledge that his model was supposed to accommodate the possible presence of 20 different amino acids in the protein chain. At this time, in 1948, he decided to ignore their differences and assumed them to be equivalent for the purpose of his model. This was yet another example of Pauling’s ability to distinguish between essential features and those that could be ignored in building his models.

“Pauling remembered a theorem in mathematics he learned about at Caltech a quarter of a century before. It stated that the most general operation to convert an asymmetric object into an equivalent asymmetric object is a rotation–translation and that repeated application of this operation produces a helix. Here the asymmetric objects are the amino acids constituting the protein chain; the rotation should take place about the molecular axis of the protein; and the translation is the movement ahead along the chain. The amount of rotation was such that took the chain from one amino acid to the next while the peptide group was kept planar, and this operation was being repeated and repeated all the time. An additional restriction was keeping the adjacent peptide groups apart at a distance that corresponded to hydrogen bonding. In Pauling’s model the turn of the protein chain did not involve an integral number of amino acids—he did not consider this a requirement whereas his British counterparts did. This was yet another relaxed feature of the structure that served him well in finding the best model whereas it served as an unnecessary restriction for his competitors.

“Pauling—ever the model builder—sketched a protein chain on a piece of paper and folded the paper while looking for structures that would satisfy the assumptions he had made. He found two and called one the alpha helix and the other the gamma helix, the latter being much less probable than the former. He determined the distance between repeating units in the protein chain and noticed a marked difference between his estimation from the model and the experimental value from the diffraction pattern. This was disappointing but the model was so attractive and so sensible that Pauling had little doubt in its correctness. Nonetheless, he decided to wait with its publication until the discrepancy would be understood. His confidence was enhanced when he visited the British group involved also in the structure elucidation of proteins and Max Perutz showed him his diffraction patters. From the X-ray diagrams it was obvious to Pauling—though not yet to Perutz—that the structure was alpha helix. Pauling did not say anything to Perutz.

“When Pauling returned to Pasadena, he and his associates double checked all his calculations and found no errors in them. In the meantime, after about a year, Bragg, Perutz, and John Kendrew of Cambridge, UK, published a big article about protein structures and communicated about 20 models, none of which contained a planar peptide group and none of which described alpha keratin satisfactorily. Finally, Pauling decided to ignore the discrepancy of the repeat distance between his model and the experimental observation and he and his associates published the alpha helix.

“Eventually, the origin of the discrepancy was under- stood; it was caused by the alpha helices twisting together into ropes. This interaction between the chains caused a change in the experimental data as compared to what it would be for a single chain for which the model had been constructed. Thus, Pauling’s alpha helix was confirmed even in this detail. The alpha helix has proved to be a great discovery because it is a conspicuously frequent structural feature of proteins.

“Pauling’s approach to solving this complex problem was exemplary in focusing on what was essential and ignoring what had little consequence. When it turned out that the turn about the chain did not correspond to an integer number of amino acids, hinting at less than perfect symmetry, he did not let himself bothered by this. He thus expanded the realm of crystallography toward structures that were not part of classical crystallography yet included literally vital substances. It was also noteworthy that he could skip a decade in working on this most important discovery without much danger of others scooping him. They almost did, but only in their timing and not in knowledge, because his knowledge proved to be superior to anyone in his field at that time.

“Pauling must have sensed the precarious nature of the situation and restrained himself from revealing crucial information to Perutz during his visit to Cambridge. The Cambridge X-ray diffraction pattern showed the helical nature but Perutz did not think about it and thus did not notice it whereas for Pauling it provided additional evidence of the correctness of his model. This episode showed both his competitive spirit and his self-discipline. Finally, Pauling was sure enough in himself and his model that he went ahead with publishing the alpha helix without having yet resolved the remaining (apparent) discrepancy between his model and the available experimental evidence. First, they published a short note, followed by a longer article [the first article offered here] and soon they wrote seven more papers to report their findings” (Hargittai).

“The most revolutionary of these articles is the first, submitted to PNAS on Pauling’s 50th birthday, February 28th, 1951. It is ‘The Structure of Proteins: Two Hydrogen-Bonded Helical Configurations of the Polypeptide Chain,’ in which Pauling and Corey are joined by a third coauthor, H. R. Branson, an African-American physicist, then on leave from his faculty position at Howard University. In the opening paragraph, the authors state that ‘we have been attacking the problem of the structure of proteins in several ways. One of these ways is the complete and accurate determination of the crystal structure of amino acids, peptides, and other simple substances related to proteins, in order that information about interatomic distances, bond angles, and other configurational parameters might be obtained that would permit the reliable prediction of reasonable configurations of the polypeptide chain.’ In other words, the structural chemist Pauling believed that with an accurate parts list for proteins in hand he would be able to infer major aspects of their overall architecture, and this proved to be so.

“The next two paragraphs concisely set out the method … the authors sought all possible repeating structures (helices) in which the carbonyl CO group of each amino acid residue accepts an N—H hydrogen bond from another residue. Why did they believe that there would be only a small number of types of helices? This was because of the constraints on structure imposed by the precise bond lengths bond angles they had found from their past studies of crystal structures of amino acids and peptides, the components from which proteins are built up. These constraints are summarized in the third paragraph of their paper, which specifies to three significant figures the bond lengths and bond angles that they had found. The most important constraint was that all six atoms of the amide (or peptide) group, which joins each amino acid residue to the next in the protein chain, lie in a single plane. Pauling had predicted planar peptide groups because of resonance of electrons between the double bond of the carbonyl group and the amide C—N bond of the peptide group. In fact, such planar peptide groups had been observed in the crystal structures of N-acetylglycine and β-glycylglycine. As the authors put it: ‘This structural feature has been verified for each of the amides that we have studied. Moreover, the resonance theory is now so well grounded and its experimental substantiation so extensive that there can be no doubt whatever about its application to the amide group.’

“When Pauling, Corey, and Branson constructed helices with planar amide groups, with the precise bond dimensions they had observed in crystal structures, and with linear hydrogen bonds of length 2.72 Å, they found there were only two possibilities. These two they called the helix with 3.7 residues per turn and the helix with 5.1 residues per turn, soon to be called the α-helix and the γ-helix.

“Much of the rest of this short, brilliant paper is taken up with a comparison of these two helices with helices proposed earlier by others, most notably Bragg, Kendrew, and Perutz in a paper the year before, that attempted to enumerate all possible protein helices, but missed these two. In their α-helix paper, Pauling et al. take a tone of triumph: ‘None of these authors propose either our 3.7-residue helix or our 5.1-residue helix. On the other hand, we would eliminate by our basic postulates all of the structures proposed by them. The reason for the difference in results obtained by other investigators and by us through essentially similar arguments is that both Bragg and his collaborators... discussed in detail only helical structures with an integral number of residues per turn, and moreover assume only a rough approximation to the requirements about interatomic distances bond angles, and planarity of the conjugated amide group, as given by our investigations of simpler substances. We contend that these stereochemical features must be very closely retained in stable configurations of polypeptide chains in proteins, and that there is no special stability associated with an integral number of residues per turn in the helical molecule.’ In short, stereochemistry is important in determining which helices are possible, and integral symmetry has no role whatever …

“The remaining six articles in PNAS give the atomic coordinates of the models and interpret the diffraction patterns of fibrous proteins in terms of the models. There is much in these papers than has not been borne out, including a proposal that muscle contraction is a transition from extended β-strands to compact α-helices. Nevertheless, the breathtaking correctness of the α-helix and β-sheets and the bold approach of modeling biological structures from chemical principles overshadow the rest” (Eisenberg).

The last two offered papers provide further refinements and summaries of the work described in the 1951 papers.

In the first, the authors note: “Crystals of several amino-acids and of a few simple peptides and other compounds related to proteins have been analyzed recently by three-dimensional methods. These and other accurate determinations of structure constitute the best experimental sources of information about the dimensions and configuration of the polypeptide chain. The present paper comprises a critical summary of this information—in particular, of the principal structural features of the amide group and the N—H—0 hydrogen bonds, as derived from X-ray diffraction analyses of crystals of amino-acids, peptides, and other organic compounds.”

“Stable Configurations of Polypeptide Chains” is an extensive summary account of their work on protein structure. It became one of the most heavily cited of Pauling’s publications.

These offprints were produced in two version, in stiff brown wrappers and in paper wrappers as here (the text on the wrappers is identical in the two versions). Presumably the publisher issued a small number of copies in the more expensive stiff wrappers and more, if required, in paper wrappers.

Eisenberg, ‘The discovery of the α-helix and β-sheet, the principal structural features of proteins,’ Proceedings of the National Academy of Sciences 100 (2003), 11207-11210. Hargittai, ‘Linus Pauling’s Quest for the Structure of Proteins,’ Structural Chemistry 21 (2010), pp. 1-7.

Two offprints, 8vo (217 x 140 mm), pp. 205-211, 235-285; 10-33. Original printed wrappers.

Item #6553

Price: $5,000.00