Linus Pauling - M. Perutz, Nature Structural Biology

Paul Mc Laughlin p.mclaughlin at ed.ac.uk
Fri Apr 28 14:12:37 EST 1995

Max Perutz would like to contribute the following, which appeared first in Nature Structural Biology,
(Volume 1(10), October 1994) to bionet.xtallography, by kind permission of the publishers.

Linus Pauling (1901 - 1994)

M.F. Perutz

Like Michael Faraday, Linus Pauling was born poor; he struggled at menial jobs to support himself
at high school and while studying for a degree in chemical engineering at the Oregon Agricultural
College. All the same, he became interested in the electron theory of valence when he was only
eighteen, and after this he "continued to hope that the empirical information about the properties of
substances could eventually be encompassed in a theory of the structure of molecules". Fulfilment of
his hope began to take shape in 1926 when he spent a postdoctoral year at Munich with Germany's
greatest teacher of theoretical physics, Arnold Sommerfeld, just as Erwin Schrödinger published his
first papers on wave mechanics. Sommerfeld immediately recognized their importance and gave a
course of lectures on them. Having absorbed what knowledge he could in Munich, Pauling next
went to Zürich to work with Schrödinger himself, but found his stay disappointing, because
Schrödinger liked to work all by himself and took little notice of him. Pauling then returned to
California Institute of Technology at Pasadena where he had taken his doctoral degree and started his
work on the nature of the chemical bond.

Part of Pauling's PhD thesis was on the structure of the mineral molybdenite (MOS2) which he
determined by X-ray analysis. After this, minerals became his first interest; he became intrigued
especially by the silicates whose complex structures formed the pride of W.L. Bragg's school at
Manchester in the nineteen-twenties. In 1929 Pauling formulated a set of simple rules, based on
ionic charges and radii, which allowed the structures of the silicates and of many other minerals to be
understood and often predicted. With these rules he put an entire subject on a rational chemical basis.

There followed a series of papers on the chemical bond. One of the first of these was revolutionary,
because it explained the tetra-hedral coordination of carbon and the square or octahedral coordination
of transition metals on wave mechanical principles. The introduction conveys something of the
flavour of his paper: "During the last 4 years the problem of the nature of the chemical bond has been
attacked by theoretical physicists, especially Heitler and London, by the application of quantum
mechanics. This work has led to an approximate theoretical calculation of the energy of formation
and other properties of very simple molecules, such as H2, and has also provided a formal
justification for the rules set up in part by G.N. Lewis for the electron pair bond. In the following
paper it will be shown that many more results of chemical significance can be obtained from the
quantum mechanics equation, permitting the formulation of an extensive set of rules for the
electron-pair bond supplementing those of Lewis. Those rules provide information regarding the
relative strengths of bonds formed by different atoms, the angles between bonds, free rotation or
lack of free rotation about bond axes, the relation between the quantum numbers of bonding
electrons and the number and spatial arrangement of bonds, etc. A complete theory of the magnetic
moments of molecules and complex ions is also developed, and it is shown that for many
compounds involving elements of the transition group this theory together with the rules of electron
pair bonds leads to a unique assignment of electron structures as well as a definite determination of
the type of bonds involved". Nothing like this had been done before.

In a later paper Pauling applied to chemistry the concept of resonance originally introduced by
Heisenberg into quantum mechanics. "It is found that there are many substances whose properties
cannot be accounted for by means of a single electronic structure of the valence bond type, but which
can be fitted into the scheme of classical valence theory by the consideration of resonance among two
or more structures". Benzene was the prime example.

Pauling's valence bond theory established the relationship between interatomic distances, mostly
derived from accurate crystallographic data, and bond energies, on which much of his successful
interpretation of the chemical properties of organic compounds was based. With that in mind, he
founded at Pasadena an outstanding research school of structural chemistry. Pauling's Munich
experience also led him to write an Introduction to Quantum Mechanics for chemists together with E.
Bright Wilson, which was first published in 1935 and remains a useful classic. 

As a chemistry student in Vienna in the nineteen thirties I had been made to memorise the 759 pages
of Karl Hoffman's Inorganic Chemistry and the 866 pages of Paul Karrer's Organic Chemistry. I
looked upon such tasks as feats of endurance which gave me a certain sporting satisfaction, like
walking from Land's End to John O'Groat's, but they gave me little intellectual satisfaction, because
the books did not explain the properties of matter. Why does water freeze at 0°C and methane at
-184°C? Why does one form of selenium melt at a temperature 76°C higher than the other? Why is
sulphur soft and diamond hard? Why is one form of silica, quartz, optically active, while the two
others, tridymite and crystoballite, are not? Why is salicylic acid stronger than benzoic acid? No such
questions were answered for me.

In 1936 I became a research student in X-ray crystallography at Cambridge. For Christmas 1939 a
girl friend gave me a book token which I used to buy Linus Pauling's recently published Nature of
the Chemical Bond. His book transformed the chemical flatland of my earlier textbooks into a world
of three-dimensional structures. It stated that "the properties of a substance depend in part upon the
type of bonds between its atoms and in part on the atomic arrangement and the distribution of
bonds", and it proceeded to illustrate this theme with many striking examples. For instance, Pauling
discusses the cause of a discontinuity in the melting points of the fluorides of the second row
elements thus: "An abrupt change in properties in a series of compounds, such as in the melting
points or boiling points of metal halides, has sometimes been considered to indicate an abrupt change
in bond type. Thus of the fluorides of the second-row elements, those of high melting points have
been described as salts, and the others as covalent compounds; and the drop in melting point of
1100°C. in going from aluminium fluoride to silicon fluoride has been interpreted as showing that
the bonds change sharply from the extreme ionic type to the extreme covalent type (1). I consider the
bonds in aluminium fluoride to be only slightly different in character from those in silicon fluoride,
and attribute the abrupt change in properties to a change in the nature of the atomic arrangements (2).
In NaF, MgF2 and AlF3 each of the metal atoms is surrounded by an octahedron of fluorine atoms,
and the stoichiometric relations then require that each fluorine atom be held jointly by several metal
atoms. In each of these crystals the molecules are thus combined into giant polymers, and the
processes of fusion and vaporisation can take place only by breaking the strong chemical bonds
between metal and non-metal atoms; in consequence the substances have high melting points and
boiling points. The stable coordination number of silicon relative to fluorine is, on the other hand,
four, so that the SiF4 molecule has little tendency to form polymers. The crystals of silicon fluoride
consist of SiF4 molecules piled together and held together only by weak van der Waals forces".
Characteristically for Pauling's showmanship, reference 1 is to N.V. Sidgwick's classic The
Electronic Theory of Valency, and reference 2 to one of his own papers. By such examples
Pauling's book fortified my belief, already inspired by J.D.Bernal, that knowledge of
three-dimensional structure is all-important and that the functions of living cells will never be
understood without knowing the structures of the large molecules composing them.

In my physical chemistry practical at Vienna I had had to prove to myself that acetic acid in solution
forms dimers, but it needed Pauling to drive home the importance of the hydrogen bonds that are
responsible for their formation: "Although the hydrogen bond is not strong it has great significance
in determining the properties of substances. Because of its small bond energy and the small
activation energy involved in its formation and rupture, the hydrogen bond is especially suited to
play a part in reactions occurring at normal temperatures. It has been recognised that hydrogen bonds
restrain protein molecules to their native configurations, and I believe that as the methods of
structural chemistry are further applied to physiological problems it will be found that the
significance of the hydrogen bond for physiology is greater than that of any other single structural
feature". This was a remarkable prophecy made when nothing was known as yet about protein

Pauling's imaginative approach, his synthesis of structural, theoretical and practical chemistry, his
capacity of drawing on a wide variety of observations to prove his generalisations, and his vivid
writing drew the dry facts of chemistry together into a coherent intellectual fabric for me and
thousands of other students for the first time.

I first met Pauling 10 years after I had read his book and was intrigued by his lectures, where he
would reel off the top of his head atomic radii, interatomic distances and bond energies with the
gusto of an organist playing a Bach fugue; afterwards he would look around for applause, as I had
seen Bertrand Russell do after quoting one of his elegant metaphors. Pauling's lectures reinforced
the chief message of his book: to understand the properties of molecules, not only must you know
their structures, but you must know them accurately.

Besides directing many people's research, Pauling used to deliver a freshmen's introductory course
of lectures which he first published as a textbook of General Chemistry in 1947. Its 1970 edition
contains over 900 pages; it begins with an introduction to the atomic and molecular structure of
matter, covers most important aspects of physical and inorganic chemistry, touches on the elements
of organic and biochemistry and ends with nuclear chemistry. The lectures were spectacular and
often dramatic. Jack Dunitz described one to me: A large beaker filled with what looked like water
stood on the bench. Pauling entered, picked a cube of sodium metal from a bottle, tossed it from
hand to hand (done safely if your hands are dry) and warned of its violently explosive reaction with
water. He then threw it into the beaker. As students cowered in fear of an explosion, he said
nonchalantly "but its reaction with alcohol is much milder". 

Pauling also made several important excursions into biological subjects; the first was into
immunology. He conceived the idea that antibodies adapt their structures to those of antigens by a
refolding of their polypeptide chains in solution: he was wrong, but it was a reasonable theory
before anything was known about the genetic basis of protein structure. He next became interested in
haemoglobin. Having read that Faraday found blood to be diamagnetic despite iron and oxygen
being paramagnetic, he told his student Charles Coryell to measure the magnetic susceptibility of
haemoglobin in the presence and absence of oxygen. In 1936, Coryell found oxyhaemoglobin to be
diamagnetic, and deoxyhaemoglobin to be paramagnetic with a spin of S=2. Forty years later I asked
Pauling what made him think of this experiment which later turned out to have been crucial for an
understanding of haemoglobin's function. Pauling replied that it had not been clear whether oxygen
formed a chemical bond with the iron in haemoglobin or whether it was merely being adsorbed, and
he thought that formation of a chemical bond might be accompanied by a magnetic change. In 1970 I
found that the spin transition of the iron is the trigger for the allosteric change that accompanies the
reaction of haemoglobin with oxygen.

In 1940, Linus Pauling and Max Delbrück anticipated molecular complementarity which later proved
to be the basis of DNA structure and replication. They attacked the German theoretician Pascual
Jordan, who had advanced the idea that there exists a quantum-mechanical stabilizing interaction,
operating preferentially between identical or near-identical molecules, which is important in
biological processes such as the reproduction of genes. Pauling and Delbrück pointed out that
interactions between molecules were now rather well understood and give stability to two molecules
of complementary structure in juxtaposition, rather than to two molecules with necessarily identical
structures. Complementariness should be given primary consideration in the discussion of the
specific attraction between molecules and their enzymatic synthesis.

In 1949 someone got Pauling interested in sickle cell disease, a genetic disorder affecting mainly
blacks which causes the red cells to be distorted to various sickled shapes on loss of oxygen.
Pauling suggested to his young collaborators Itano, Singer and Wells that they should examine the
electrophoretic mobilities of normal and sickle cell haemoglobin. They found them to be different,
because sickle cell haemoglobin carries two fewer negative charges than normal haemoglobin.
Pauling published this result in Science under the dramatic title: "Sickle cell haemoglobin, a
molecular disease". This paper led Vernon Ingram and John Hunt in my MRC Unit in Cambridge to
show that sickle cell haemoglobin differed from normal merely by the replacement of a single pair of
glutamic acid residues by valines. Their discovery of the effect of a genetic mutation on the amino
acid sequence of a protein posed poignantly the question of the genetic code, which Crick, Brenner
and their colleagues answered a few years later with their demonstration that triplets of nucleotides
determine the amino acid sequence of proteins.

Among biochemists, Pauling is most famous for his discovery of the alpha-helix which came as the
culmination of X-ray analyses of the structures of amino acids pioneered in the 1930s and '40s by
his collaborators Robert Corey and Edward Hughes; at that time glycine, alanine and
diketopiperazine presented a degree of complexity that carried X-ray analysis to the very limits of the
possible. The results provided Pauling with the stereochemical data he needed for the interpretation
of the meagre X-ray diffraction patterns which Bill Astbury at Leeds had obtained from protein
fibres such as hair, nails or muscle. Pauling argued that in a long chain polymer made of chemically
equivalent units, all units must occupy geometrically equivalent positions, which was possible only
in a helix. Further, the structure of diketopiperazine had shown that the peptide bond had partial
double bond character, so that the atoms

H                  O
  \              /
   \            /
   /            \ 
  /              \ 
C[alpha]1       C[alpha]2       

must all lie in a plane. Finally, all NH groups should form hydrogen bonds with COs. Lying in bed
with 'flu in Oxford in 1948, Pauling amused himself by building a paper chain of planar peptides
and found a satisfactory structure by folding them into a helix with 3.6 residues per turn. Shortly
after this he visited Kendrew and me in Cambridge. Ignorant of his Oxford experiment, I proudly
showed him my three-dimensional Patterson of haemoglobin which indicated that its polypeptide
chain was folded in the same way as Astbury's fibres, but to my disappointment Pauling made no
comment; he did not announce his discovery until the delivery of a dramatic lecture at Pasadena in
the following year. It helped to earn him the Nobel Prize in Chemistry in 1954, but he had really
deserved it for his many other outstanding contributions to chemistry much earlier.

In the same year, 1948, Pauling made another important prediction: "I think that enzymes are
molecules that are complementary in structure to the activated complexes of the reactions that they
catalyse, that is, the molecular configuration that is intermediate between the reacting substances and
the products of the reaction".

After the alpha-helix Pauling produced one more fundamental paper. When the amino acid sequences
of the haemoglobins of different animals were beginning to be known, it became clear that the
number of amino acid substitutions increased with the distance between species on the evolutionary
tree. This inspired Pauling and his young collaborator Emile Zuckerkandl to propose the existence of
an evolutionary clock which ticks at the rate of about one amino acid substitution per hundred
residues per 5 million years. Like many of Pauling's papers this one initiated an entire new field of
research which has since occupied many other scientists' lives. Pauling continued publishing papers
almost to the end of his life, but nothing as fundamental as his earlier work appeared, possibly
because he became too preoccupied, first with the threat of nuclear war and later with vitamin C. 

In the McCarthy era, Pauling's anti-nuclear stance earned him the reputation of a "red". In 1952,
when the Royal Society organized a Discussion on the Structure of Proteins at which Pauling should
have been the principal contributor, he could not come because the State Department had withdrawn
his passport. In 1954, the English philosopher Bertrand Russell gave Christmas lectures on the radio
warning of the dangers of nuclear war. Next year he drew up a manifesto against nuclear arms
which Albert Einstein signed a few days before his death. This concluded with the words: "There
lies before us, if we choose, continual progress in happiness, knowledge and wisdom. Shall we,
instead, choose death, because we cannot forget our quarrels? We appeal, as human beings, to
human beings: remember your humanity and forget the rest. If you can do so, the way lies open to a
new paradise; if you cannot, there lies before you the risk of universal death". Pauling signed this
manifesto together with seven prominent physicists and the geneticist Hermann Muller; it led to the
convening of the first Pugwash Conference at which Soviet and Western scientists discussed
measures to reduce the dangers of nuclear war. In 1958, Pauling published a book: No More War
and handed to Dag Hammarskjöld, the Secretary General of the United Nations, a petition signed by
9235 scientists "urging that an international agreement to stop the testing of nuclear weapons be
made now . . . . inasmuch as it is the scientists who have some measure of the complex factors
involved in the problem, such as the magnitude of the genetic and somatic effects of the released
radioactive materials". In May 1961 Pauling organised a conference of forty scientists on nuclear
disarmament in Oslo, and afterwards led hundreds of people in a torchlight procession against
nuclear war through the streets of Oslo. His campaign, conducted with the same panache as his
lectures on chemistry, made a vital contribution to the conclusion of the atmospheric test ban in 1963
and won him the Nobel Prize for Peace in December of that year. He also campaigned against the
war in Vietnam, undeterred by being called a traitor. 

In 1942 Pauling contracted a severe kidney disease which he thought he had cured with massive
doses of vitamin C. This may have sparked off his idea that huge doses of vitamin C were vital for
health, and that they cured the common cold and even cancer. Chemists shops in Britain still sell
vitamin C as "Linus Powder", of which he swallowed about eighteen grammes every day; probably
about 100 milligrams would have been absorbed and the rest excreted. Ascorbic acid is a scavenger
of free radicals and a deficiency of it may therefore increase the likelihood of cancer, but there is no
solid evidence that such massive doses have any prophylactic effect. To me it seems tragic that this
should have become one of Pauling's major preoccupations for the last 25 years of his life and spoilt
his great reputation as a chemist. Perhaps it was related to his greatest failing, his vanity. When
anybody contradicted Einstein, he thought it over, and if he found he was wrong, he was delighted,
because he felt he had escaped from an error, and that he now knew better than before, but Pauling
would never admit that he might have been wrong. When, after reading Pauling's and Corey's paper
on the alpha-helix, I discovered an X-ray reflection at 1.5Å spacing from planes perpendicular to the
axis of protein fibres which excluded all conformations other than the alpha-helix, I thought he
would be pleased, but no, he attacked me furiously, because he could not bear the idea that someone
else had thought of a test for the alpha-helix of which he had not thought himself. I was glad when
he forgot his anger later and became a good friend.

Pauling's fundamental contributions to chemistry cover a tremendous range, and their influence on
generations of young chemists was enormous. In the years between 1930 and 1940 he helped to
transform chemistry from a largely phenomenological subject to one based firmly on structural and
quantum mechanical principles. In later years the valence bond and resonance theories which formed
the theoretical backbone of Pauling's work were supplemented by R.S. Mulliken's molecular orbital
theory which provided a deeper understanding of chemical bonding. For instance, it allowed C.
Longuet-Higgins and W. Lipscomb to predict and explain the structures of the boranes, which
would not have been possible on the basis of Pauling's concepts. Nevertheless resonance and
hybridization have remained part of the everyday vocabulary of chemists and are still used, for
example, to explain the planarity of the peptide bond. Pauling's combination of encyclopaedic
knowledge of chemistry and imaginative intuition was unique; many of us regard him as the greatest
chemist of the century.

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