"When we look at a cell through a microscope or analyze its electrical or biochemical activity, we are, in essence, observing proteins. Proteins constitute most of a cell’s dry mass. They are not only the cell’s building blocks; they also execute the majority of the cells functions. Thus, proteins that are enzymes provide the intricate molecular surfaces inside a cell that catalyze many of its chemical reactions. Proteins embedded in the plasma membrane form channels and pumps that control the passage of small molecules into and out of the cell. Other proteins carry messages from one cell to another, or act as signal integrators that relay sets of signals inward from the plasma membrane to the cell nucleus. Yet other serve as tiny molecular machines with moving parts …. Before we can hope to understand how genes work, how muscles contract, how nerves conduct electricity, how embryos develop, or how our bodies function, we must attain a deep understanding of proteins."
–Bruce Alberts, et al., “Molecular Biology of the Cell” (6th ed. 2015)
"As scientists have found in the last fifty years, form also serves function in the invisible world of the atom. The organic molecules that make life are … complex structures that twist and turn through three-dimensional space. … When biologists began unraveling the structures of organic molecules in the 1930s, they suspected that these exquisite architectur[al] features were not simply accidents."
–Alan Lightman, “The Structure of Proteins”, in “The Discoverers” (2005)
FIRST EDITIONS, OFFPRINT ISSUES (INCLUDING ONE SIGNED COPY AND ONE SIGNED PRESENTATION COPY), OF MILESTONE PAPERS ON THE DETERMINATION OF THE STRUCTURE AND FUNCTION OF PROTEINS, WORK FOR WHICH PAULING, KENDREW, AND PERUTZ ALL WON NOBEL PRIZES.
Proteins — the “building blocks of life” - are themselves made up of building blocks known as amino acids. There are about twenty types of amino acid molecules commonly found in biological organisms, and each is chemically equipped to connect to two other amino acids through a linkage known as a peptide bond, enabling any number of amino acids to form a chain that constitutes the backbone of a protein molecule. (The specific linear sequence of amino acids that make up a particular protein’s backbone is referred to as the protein’s “primary structure.”) Each of the 20-odd amino acids also has its own characteristic “side-chain.” The interaction of these side chains with each other and with their natural environment in the cell determines how the protein will fold up after it is synthesized into a specific three-dimensional configuration that enables the protein to carry out its architectural, catalytic, or other functions. Some portions of the protein chain fold into simple, regular structural motifs such as helices and sheets. These are referred to as “secondary structure” of the protein, while the overall three-dimensional configuration of the entire protein molecule is known as its “tertiary structure.”
Because of the vital biological importance of proteins — and because the close relationship of between the biological function of a protein and its three-dimensional form — determining the details of protein structure has been one of the priorities of molecular biologists from the 1950s onward. The primary tool for unraveling the three-dimensional structure of proteins is X-ray crystallography, in which the complex diffraction patterns formed X-rays interacting with the lattice of molecules in a protein crystal can be decoded — through laborious mathematical calculations — in order to establish details of a protein’s structure. As crystallographic techniques advanced and as faster and better computers became available, scientists were able to use this tool to determine the structure of proteins down to the atomic level. (The level of detail — or “resolution” — available from X-ray diffraction data is generally expressed in Ångstrom units [abbreviated Å]. One Å is one ten-millionth of a millimeter, or about the size of a hydrogen atom.)
The papers that are offered here document key milestones in our understanding of protein structure.
(a) A single inscribed offprint (“To Bob Schindler - Linus Pauling”) containing eight papers by Linus Pauling and his collaborators, announcing the discovery of the “α-helix,” the “β-sheet,” and other important aspects of the secondary structure of proteins, as published in the April and May 1951 issues of Proceedings of the National Academy of Sciences, including “The Structure of Proteins: Two Hydrogen-Bonded Helical Configurations of the Polypeptide Chain” and “The Pleated Sheet, a New Layer Configuration of Polypeptide Chains” (1st ed. 1951; offprint issue in original wrappers; boldly inscribed by Pauling to Robert Schindler). The offprint also includes a short related paper by Pauling and R. Corey, “Two Hydrogen-Bonded Spiral Configurations of the Polypeptide Chain”, originally published in in 1950 in the Journal of the American Chemical Society.
“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).
In these papers, Pauling postulated the existence of the “α-helix” as a recurring structural motif in proteins. “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 the 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 the 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.” David Eisenberg, “The Discovery of the α-Helix and the β-Sheet, the Principal Structural Features of Proteins,” in Proceedings of the National Academy of Sciences 100:11207-10 (2003). “These papers are all the more remarkable when we consider the political context in which they were written. During this period, Pauling was also heavily involved in defending academics, including himself, against charges of disloyalty to the United States, brought about by the pressures of the Cold War and what became known as McCarthyism. … On the day after Pauling and Corey submitted their seven protein papers for publication, the House Un-American Activities Committee named Pauling one of the foremost Americans involved in a ‘Campaign to Disarm and Defeat the United States.’ … Somehow, even in the face of such false invective and multiple distractions, Pauling could maintain his focus as a top creative scientist.” Id.
Pauling won the Nobel Prize in Chemistry in 1954 “for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances.” The presentation speech for Pauling’s award referred to his “deduc[tion of] some possible structures of the fundamental units in proteins,” and noted that it had “become apparent that one of these structures, the so-called alpha-helix, probably exists in several proteins.” (Since 1954, “probably” has become “beyond a doubt.”)
(b) Kendrew, John, “A Three-Dimensional Model of the Myoglobin Molecule Obtained by X-Ray Analysis”, in Nature (1st ed., offprint issue, 1958), with Kendrew, John, et al., “Structure of Myoglobin: A Three-Dimensional Fourier Synthesis at 2 Å Resolution”, in Nature (1st ed., offprint issue, 1960).
These papers reported the first determination of the complete tertiary structure of a protein molecule — the muscle protein myoglobin — work for which Kendrew received the 1962 Nobel Prize in Chemistry. Kendrew unraveled the structure through X-ray crystallography, making use of the heavy-atom replacement method developed by Perutz for his investigations of hemoglobin structure (see next listing below). “Kendrew, working on the smaller myoglobin molecule, was the first to take full advantage of the new method. In 1958, he presented the first model ever of a globular protein derived by direct structure determination. The model showed the general outline of the molecule; a second model at atomic resolution followed two years later [the two papers offered here].” — Dictionary of Scientific Biography.
These two papers are offered with a collection of seventeen additional offprints of papers by Kendrew on myoglobin, hemoglobin, and various aspects of protein structure. One of these is a presentation copy signed by Kendrew; three are from the library of Peter Pauling (1931-2003, a crystallographer and Linus Pauling’s son), with his signature; and one is from the library of Max Perutz, with his ownership stamp.
(c) Perutz, Max F., “Structure of Haemoglobin. A Three-Dimensional Fourier Synthesis at 5.5-Å Resolution, Obtained by X-Ray Analysis”, in Nature (1st ed., offprint issue, 1960; signed by Perutz). This paper was published back-to-back with Kendrew’s 1960 paper on myoglobin structure (above) in the February 13, 1960 issue of Nature.
“Perutz dedicated a large part of his long scientific career to unraveling the molecular structure and function of hemoglobin, the protein of red blood cells. In this work he made pioneering use of xray crystallography. He was a corecipient of the 1962 Nobel Prize for Chemistry and the founder and first chairman of the Medical Research Council Laboratory of Molecular Biology in Cambridge, which produced a string of Nobel Prize winners.” — Dictionary of Scientific Biography.
“In 1954, David Green, Vernon Ingram and Perutz published the seminal paper describing how, in principle, X-ray diffraction could be used for the direct determination of a protein structure. To obtain the crucial phases, Perutz and his colleagues … introduced ‘heavy’ atoms (in this case mercury) into the haemoglobin crystal …. Comparing the differences in intensities between the diffraction spots from a heavy-atom-containing crystal and the normal crystal allowed them to determine the location of the mercury atoms and from that information the phases of the X-rays — solving the so-called ‘phase problem.’ … It would have seemed from this breakthrough that the structure determination of haemoglobin was just around the corner. In fact, it took six years of hard work before Perutz was able to publish the structure of haemoglobin, at a resolution of 5.5 Å.” Rebecca Kirk, “Nature Milestones in Crystallography. Milestone 12: First Atomic-Level Protein Structure” (July 17, 2014).
“Perutz (1914-2002), a native of Austria, was an avid alpinist in his youth. In an interview he once compared making scientific discoveries to summiting a peak: ‘When you get to the top after a hard climb, a view of a new landscape opens before you.’ This is certainly an apt metaphor to describe the impact of his research on the structural basis of Hb [hemoglobin] allostery. [Allostery refers to the phenomenon — vital to the proper functioning of hemoglobin — by which the attachment of an oxygen molecule to hemoglobin promotes the attachment of additional oxygen molecules at other sites on the protein.] The fact that it is possible to explain allosteric mechanisms of Hb function in terms of atomic level interactions [within the molecule] is one of the great triumphs of twentieth-century molecular biology and protein science. As stated by Bunn and Forget … ‘If the hemoglobin story has a hero, it is Max Perutz.’” Jay F. Storz, “Hemoglobin: Insights Into Protein Structure, Function, and Evolution” (2019).
(d) “A Discussion of the Structure and Function of Lysozyme: Organized by M.F. Perutz, F.R.S.”, in Proceedings of the Royal Society (1at ed. 1967, journal issue in original wrappers).
Enzymes are biological catalysts whose activity is essential to the metabolic processes of an organism. “Lysozyme was the second protein and the first enzyme structure to be solved by X-ray diffraction methods. … [T]he first public presentation of the structure [was] made … at a Friday Evening discourse held at the Royal Institution, London, on the 5th of November 1965.” Louise N. Johnson, “The Early History of Lysozyme,” in Nature Structural Biology 5:942-44 (1998). More importantly, the determination of lysozyme’s structure provided key insights into how enzymes work. John Rupley of the University of Arizona was able to grow crystals of the complexes formed when lysozyme temporarily combined with the large sugar molecules whose dissociation is catalyzed by the enzyme (the enzyme’s “substrate”). X-ray diffraction data obtained from the crystals was then used by Louise Johnson and David Phillips to build a model of the enzyme-substrate complex, and the structural data embodied in the model provided immediate insights into the elegant mechanism by which the enzyme worked. “[T]he mechanism, which has now become a classic, was presented at the Royal Society meeting on the 3rd of February, 1966. As Max Perutz commented in his closing remarks at the meeting: ‘For the first time we have been able to interpret the catalytic activity of an enzyme in stereochemical terms.’” Id. The issue of the Proceedings offered here contains the thirteen papers read at the February 3 meeting, bookended by an introduction by Sir Lawrence Bragg, a pioneer in the use of X-ray crystallography, and concluding remarks by Max Perutz, quoted above.
Also included in this same issue of the Proceedings — although not immediately relevant to protein structure — is Francis Crick’s 1966 Croonian Lecture, “The Genetic Code.” (The Croonian Lectures are “the premier lecture[s] in the biological sciences and [are] delivered annually at the Royal Society in London.” — Royal Society web site, royalsociety.org) Crick’s lecture summarized recent work aimed at unraveling how the sequence of “base pairs” in the DNA molecule encodes the primary structure of a protein molecule. It had been determined that each amino acid in a protein molecule is specified by a triplet of consecutive base pairs in the DNA molecule (a “codon”); the remaining task was to determine which codons specified which amino acids — in other words, to break the “genetic code.” “By May 1966 all but one codon had been cracked . . . . On May 5, Crick delivered the Royal Society’s Croonian Lecture, setting out all the steps in the deciphering of the code and triumphantly unveiling the final chart, minus that one recalcitrant UGA assignment. Those who attended his Croonian lecture left with a sense of history in the making.” “The possibility of a simple code at the heart of all biology, promised by the structure of the double helix, was now an established fact.” Matt Ridley, “Francis Crick: Discoverer of the Genetic Code” (2006). (The “recalcitrant assignment” referred to by Ridley was the determination of what amino acid was associated with the codon corresponding to the messenger RNA sequence uracil-guanine-adenine [UGA]. It turned out to be a trick question — UGA did not specify any amino acid; instead, it was a “stop” or “termination” single. The fact that there are 64 possible codons and only twenty-odd amino acids allows for redundancy in the genetic code — thus reducing the risk that mutations will have dangerous consequences — while also leaving room for “punctuation” such as the stop codon.)
(e) Perutz, M. F., “The Croonian Lecture, 1968. The haemoglobin molecule”, in Proceedings of the Royal Society (1st ed. 1969, journal issue with original wrappers). Summary of Perutz’ work on hemoglobin structure.
These original published reports of key research in molecular biology are offered with the December 1961 issue of Scientific American, which includes an article by Kendrew (“Three-Dimensional Structure of a Protein”) discussing — only a year after its original publication — the high-resolution myoglobin structure he had discovered. The article includes a striking page-and-a-half painting of the structure by Irving Geis. “Nowadays one can easily create an image of a proteins structure with the aid of a computer and molecular visualization software. In 1961, however, everything had to be done by hand. Creating an image of a proteins structure required not only outstanding artistic skills of visualizing complicated 3D structures, but also extraordinary patience. Originally trained as an architect …, Geis had all the skills and knowledge to visualize the 3D structures of proteins. Geis created this painting by first photographing the physical models and then by creating voluminous sketches and studies before painting the final version. A lot of refinements were made during the sketch step based on the feedback from John Kendrew …. The final painting took 6 months to complete.” Yan Liang, “Irving Geis and His Paintings of Proteins”. By the criteria of elegance, beauty, explanatory power, and density of information content, Geis’ colorful depiction of the position of each atom and atomic bond in myoglobin deserves to rank with Hooke’s flea in “Micrographia” and Galileo’s drawings of the moon in “Sidereus Nuncius” among the greatest scientific illustrations of all time.
Pauling, Linus, R. Cory, and H.R. Branson, “The Structure of Proteins: Two Hydrogen-Bonded Helical Configurations of the Polypeptide Chain” (1951), (b) Pauling, Linus and R. Corey, “The Pleated Sheet, a New Layer Configuration of Polypeptide Chains” (1951), (c) Kendrew, John, “A Three-Dimensional Model of the Myoglobin Molecule Obtained by X-Ray Analysis” (1958), (d) Kendrew, John, et al., “Structure of Myoglobin: A Three-Dimensional Fourier Synthesis at 2 Å Resolution” (1960); (e) Perutz, Max F., “Structure of Haemoglobin. A Three-Dimensional Fourier Synthesis at 5.5-Å Resolution, Obtained by X-Ray Analysis,” and numerous other papers.
A REMARKABLE COLLECTION, WITH ALL PAPERS AND OFFPRINTS IN ORIGINAL WRAPPERS IN FINE CONDITION.
Price: $28,000 .