Linus Pauling 1901–1994

Important discoveries arise out of the confluence of various individual, historical and scientific factors. When these factors come together in the life and work of an individual of genius such as Linus Pauling, the discoveries may open up new fields for exploration by breaking down boun daries be tween indepen dent disci plines. Two examples of Pauling's pathbreaking work at the frontier of physics and chemistry are his early research in 1922 with Roscoe Dick in son in X- ray diffraction methods for determining the structures of min erals, and his European studies in 1926 in the new wave mech an ics. The first led to the five rules for stability of complex ionic crystals [1xThe coordination theory of the structure of ionic crystals. Pauling, L. Festschrift zum 60. Geburstag Arnold Sommerfelds. 1928; 53: 1367–1400See all References[1], and the second to the remarkable paper on chemical bonds, directed orbitals, stereochemistry, and magnetic properties of transition metal complexes [2xThe nature of the chemical bond. Application of results obtained from the quantum mechanics and from a theory of paramagnetic susceptibility to the structures of molecules. Pauling, L. J. Am. Chem. Soc. 1931; 53: 1367–1400CrossrefSee all References[2]. On the border between chemistry and biology, the first of many contributions to the function of hemoglobin appeared in 1935 [[3]xThe oxygen equilibrium of hemoglobin and its structural interpretation. Pauling, L. Science. 1935; 81: 421See all References, [4]xThe oxygen equilibrium of hemoglobin and its structural interpretation. Pauling, L. Proc. Natl. Acad. Sci. USA. 1935; 21: 186–191Crossref | PubMedSee all References] and in the following year Pauling and Charles Coryell showed that the uptake of oxygen changed the magnetic state of the iron from paramagnetic to diamagnetic, thus indi cating a direct interaction between oxygen and the ferrous ion.Working as he did at the edge of known science, Pauling ran the risk of occasionally being wrong, but even then his work pointed to fertile areas for future research. In the period 1936– 1939 conversations with Karl Landsteiner led Pauling to carry out many subsequent studies of hapten– antibody reactions (with Dan H Campbell and David Pressman). However, Pauling's proposal for the process of folding of antibodies so that they became complementary to antigens [5xA theory of the structure and the process of formation of antibodies. Pauling, L. J. Am. Chem. Soc. 1940; 62: 2643–2657CrossrefSee all References[5] was later shown to be a more complex process which involved both molecular recognition and genetic selection. Nevertheless, the basic idea of molecular complementarity mediated by the weak forces such as hydrogen bonds, salt links, dipolar forces and van der Waals forces in biological systems became a central theme of later structural investigations by Pauling and by others whom he influenced.It was my privilege to be at Caltech during 1941– 1946 and to hear Pauling's lectures and to be directed in research by him as well as by Edward W Hughes, Verner Schomaker, James H Sturdi vant and Robert B Corey. His lectures were per formances: an easy first third, a masterful second third and a challenging final third — in short, a model of inspiring teaching. Occasionally, he would sit or lie on the laboratory bench to “improve the circulation in his brain”, and sometimes in the quantum mechanics course he would arrive carefully prepared with a ‘spontaneous’ answer to an anticipated question. Most of us attended the lectures on chem i cal bonding year after year, since new material was continually being presen ted. From Pauling, I learned how to choose in teresting and significant re search problems, how to build a solid background of well-established facts, and how to make intuitive leaps of conjecture [6xThe genesis of ideas. Pauling, L. : 44–47See all References[6] which were then subjected to in tense scrutiny. An occasional mistake, even when published, was not as bad as lowering one's sights to less challenging research. In the spring of 1946, near the end of my stay at Caltech, Pauling suggested that I use the then new electron microscope at Berkeley to obtain images of hapten– antibody complexes. Although the resolution was not sufficient for a successful result, the experiment demonstrated Pauling's early recognition of the potential of the electron microscope for structural studies in biochemistry.In 1932, Pauling deduced the planarity of amide groups, and this was later supported by Robert Corey's structure of diketopiperazine [7xSee all References[7]. In 1948, Pauling was ill with influenza in Oxford when he drew a polypeptide chain on paper and folded it at the Cα positions to make a helical structure containing planar peptide linkages and having 3.6 amino acid residues per turn. A major departure from all previous proposals was the conclusion that there need not be an integral number of amino acids per turn of helix. Following a preliminary account in 1950 [8xTwo hydrogen-bonded spiral configurations of the polypeptide chain. Pauling, L. and Corey, R.B. J. Am. Chem. Soc. 1950; 72: 5349CrossrefSee all References[8] and a longer paper in 1951 [9xTwo hydrogen-bonded helical configurations of the polypeptide chain. Pauling, L., Corey, R.B., and Branson, H.R. Proc. Natl. Acad. Sci. USA. 1951; 37: 205–210Crossref | PubMedSee all References[9], there appeared a series of seven papers, including the β-sheet structures, which transformed (and greatly increased!) the contents of the Proceedings of the National Academy of Sciences relating to biochemistry and molecular biology. Immediate experimental support for the α-helical structure was found by Max Perutz in the 1.5 a spacing of oriented fibrous proteins. Later detailed studies of protein structures showed them to have α-helical contents averaging about one-third of the organized structure, although the content varies from zero to about 85% among different globular protein structures.Pauling also contributed to transition state theory. In 1930, JBS Haldane [10xHaldane, J.B.S. : 182See all References[10] amended Emil Fischer's lock (enzyme) and key (substrate) model to say, “using Fischer's lock and key simile, the key does not fit the lock perfectly, but exercises a certain strain on it.” In 1948, Pauling made a more precise statement which incorporated the beginning of the chemical transformation along the reaction pathway [11xThe nature of forces between large molecules of biological interest. Pauling, L. Nature. 1948; 161: 707–709Crossref | PubMedSee all References[11]: ‘I think that enzymes are molecules that are complementary in structure to the activated complexes of the reactions that they catalyze.” This formulation became a significant stimulus to the study of enzyme mechanisms and the design of organic molecules which inhibit specific enzymes as a ‘rational’ method of drug design.Another major contribution was to our understanding of the origins of molecular disease. Pauling became aware of the sickle-cell anemia problem in 1945 during a lecture by William Castle. This disease is caused by aggregation of abnormal hemoglobin molecules within the erythrocyte at low oxygen pressures. Pauling and his coworkers [12xSickle cell anemia, a molecular disease. Pauling, L., Itano, H.A., Singer, S.J., and Wells, I.C. Science. 1949; 109: 443PubMedSee all References[12] showed that the hemoglobins from normal and sickle cells had different mobilities and suggested that there were differences between the numbers of acidic or basic groups within the hemoglobin molecule. These differences were thought to influence the aggregation of the abnormal hemoglobin. In this study they identified for the first time a molecular disease. Soon thereafter, Vernon Ingram [13xA specific chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin. Ingram, V.M. Nature. 1956; 178: 792–794Crossref | PubMed | Scopus (295)See all References[13] showed that Glu6 in the β-chain of hemoglobin was replaced by valine. In a later study of mutations [14xMolecular disease, evolution and genic heterogenetity. In. Zuckerkandl, E. and Pauling, L. : 189–225See all References[14], Emil Zuckerkandl and Pauling related the diverse fields of molecular biology, genetics and paleontology by the proposal that changes in amino acid sequences in hemoglobin were associated with the times of divergence in evolution.A fitting tribute to Pauling ”s achievements is given in the words of Francis Crick [15xThe impact of Linus Pauling on molecular biology: a reminiscence. Crick, F. : 87–98See all References[15]: “It was because of Linus Pauling that our approach to the structural side of things had the character that it had, and it was successful because he had the right set of ideas. So we should salute Linus Pauling not only for the wonderful things that he has done for chemistry and in particular his realizing the importance of quantum mechanics for chemistry and applying it as a chemist (as opposed to just a theorist) — but also for his absolute seminal role in getting molecular biology started.” .Figure 1Linus Pauling in 1946. Photographs courtesy of William Lipscomb.View Large Image | View Hi-Res Image | Download PowerPoint SlideFigure 2Linus Pauling in 1985. Photographs courtesy of William Lipscomb.View Large Image | View Hi-Res Image | Download PowerPoint Slide