When, in the early nineteenth century, Dalton had produced experimental proofs that matter consists of atoms it was not long before an explanation was sought of the forces that bind the atoms together. Berzelius was of the opinion that this chemical bond was caused by electrostatic attraction between the atoms; according to this belief, a bond was established between two atoms if one of the atoms was positively, and the other negatively charged. In 1819 when Berzelius presented his theory he could apply it almost exclusively to inorganic substances; only few organic substances were known as pure compounds, and the study of these was difficult due to their complicated and often insufficiently known composition. Berzelius, however, contrived to explain, with the help of the new theory, the bond conditions for a great number of inorganic substances, and could in this wav contribute in a high degree to a greater clarity in this field.
...For a long time it was difficult to explain the nature of the covalent bond. Lewis, however, succeeded in 1916 in showing that it is brought about by electrons - generally two - which are shared in common by two neighbouring atoms, thereby uniting them. Eleven years later Heitler and London were able to give a quantum-mechanical explanation of the phenomenon. An exact mathematical treatment of the covalent bond, however, was possible only in the simple case where only one electron unites the two atoms, and when these do not contain additional electrons outside the atomic nuclei. Even for the hydrogen molecule, which contains two electrons, the treatment cannot be absolutely exact, and in still more complicated cases the mathematical difficulties increase rapidly. It has, therefore, been necessary to use approximate methods, and the results depend to a large extent on the choice of suitable methods and the manner of their application.
Linus Pauling has actively contributed towards the development of these methods, and he has applied them with extreme skill. The results have been such as to be easily usable by chemists. Pauling has also eagerly sought to apply his views to a number of structures which have been experimentally determined during the last decades, both in his own laboratory in Pasadena and elsewhere. It is hardly necessary to mention that we have nowadays great possibilities of reaching Blomstrand's objective of determining the distribution of atoms in space. This is principally done by methods of X-ray crystallography involving an examination of how a crystal
Linus Pauling, Nobel Prize in chemistry 1954, California Institute of Technology (Caltech)
Pasadena, CA, USA. b 1901, d. 1994
influences X-rays in certain respects, and then out of the effect seeking to determine how the atoms are placed in the crystal. Pauling's methods have been very successful and have led to observations which have further advanced the theoretical treatment. But if the structure of a substance is too complicated it may become impossible to make a more direct determination of the structure with X-rays. In such cases it may be possible, from a knowledge of bond types, atomic distances and bond directions, to predict the structure and then examine whether the prediction is supported by the experiments. Pauling has tried this method in his studies of the structure of proteins with which he has been occupied during recent years. To make a direct determination of the structure of a protein by X-ray methods is out of the question for the present, owing to the enormous number of atoms in the molecule. A molecule of the coloured blood constituent hemoglobin, which is a protein, contains for example more than 8,000 atoms.
In the late nineteen thirties Pauling and his colleagues had already begun to determine with X-rays the structure of amino acids and dipeptides, that is to say, compounds of relatively simple structure containing what may be called fragments of proteins. From this were obtained valuable information - about atomic distances and bond directions. These values were supplemented by the determination of the probable limits of variation for distances and directions.
On this basis Pauling deduced some possible structures of the fundamental units in proteins, and the problem was then to examine whether these could explain the X-ray data obtained. It has thus become apparent that one of these structures, the so-called alpha-helix, probably exists in several proteins.
Max Ferdinand Perutz (b. 1914, d. 2002) and John Cowdery Kendrew (b. 1917, d. 1997). Nobel Prize in Chemistry 1962. MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
...by about the middle of the 1940's a point had been reached where it was becoming possible to carry out X-ray determinations of the structures of organic compounds which were so complicated that they defied all attempts using classical chemical methods....
...In 1937 Max Perutz performed some experiments in Cambridge to find out whether it might be possible to determine the structure of haemoglobin by X-ray diffraction, since no other method could be imagined for this purpose. Sir Lawrence Bragg, who tirelessly continued the work begun jointly with his father, in 1938 became the head of the Cavendish Laboratory in Cambridge. When he saw the results obtained by Perutz, he encouraged him to continue and has ever since lent a very efficient support.
...About ten years later, John Kendrew joined Perutz' research group, and the task allotted to him was to try to determine the structure of myoglobin.
...However, Perutz and Kendrew encountered considerable difficulties. In spite of exceptionally comprehensive work, the result was not forthcoming until 1953, when Perutz succeeded in incorporating heavy atoms, namely those of mercury, into definite positions in the haemoglobin molecule. By this means the diffraction pattern is altered to some extent, and the changes can be utilized in a more direct structure determination. The method was already known in principle, but Perutz applied it in a new way, and with great skill.
As a result of Kendrew's and Perutz' contributions it is thus becoming possible to see the principles behind the construction of globular proteins. The goal has been reached after twenty-five years' labour, and initially with only modest results. We therefore admire the two scientists not only for the ingenuity and skill with which they have carried out their work, but also for their patience and perseverance, which have overcome the difficulties which initially seemed insuperable. We now know that the structure of proteins can be determined, and it is certain that a number of new determinations will soon be carried out, perhaps chicfly following the lines which Perutz and Kendrew have indicated.
Exactly 50 years ago, a Nobel Prize was awarded which we have much reason to be reminded of today. Max von Laue was awarded the 1914 Nobel Prize for physics for, according to the citation, "his discovery of the diffraction of X-rays by crystals". It is this phenomenon which has formed the basis of the work for which Mrs. Dorothy Crowfoot Hodgkin has been awarded the Nobel Prize for chemistry this year.
However, even today structure determination by X-ray methods does not yield a direct route from the experimental data to the structure. In complicated cases the scientist only obtains a result after considerable mental effort, in which chemical knowledge, imagination and intuition play a significant part. In addition, the experimental data often have to be processed using different mathematical treatments, which must be varied according to the circumstances. Add to this the fact that the more complicated the structure, the greater becomes the volume of experimental data which must be amassed and processed. For relatively simply built compounds it was possible to carry out the calculations with pencil and paper. Nowadays it is nearly always necessary to use electronic computers, and their arrival has made an enormous difference to the possibility of carrying out structure determinations.
Mrs. Hodgkin has carried out a large number of structure determinations, primarily of substances which are of importance biochemically and medically, but two of these substances deserve especial mention. These are penicillin and vitamin B12, whose structures have become completely and definitely known through her efforts.
....The use of penicillin in medicine began to be tested about the beginning of the second world war, and its exceptional antibiotic properties meant that the demand increased enormously. It was therefore obviously desirable to find out whether penicillin itself or other related compounds having a similar effect could be prepared by chemical methods. For this purpose it was essential to determine the composition and structure of penicillin, and a large number of chemists and X-ray crystallographers in both England and the U.S.A. were put on to this problem. Mrs. Hodgkin was to play a leading part in the X-ray crystallographic work, and it was chiefly her efforts which brought it to a satisfactory conclusion.
Dorothy Crowfoot Hodgkin (b. 1910, d. 1994), Nobel Prize in Chemistry 1964. University of Oxford, Royal Society, Oxford, United Kingdom.
In 1948 Mrs. Hodgkin began her attempts to determine the structure of vitamin B12, which had been isolated in the same year. This vitamin can be synthetized by certain bacteria and fungi, of which some play an active part in the digestive processes of animals. The production of B12 is most pronounced in the ruminants, who seem to require this vitamin in particularly large amounts. In most of the other higher animals, for example in man, the production of B12 is small, and their food must therefore contain sufficient quantities of ready-made B12. Lack of B12 in the diet, or a reduced ability to absorb this vitamin via the walls of the alimentary canal, leads in man to the fatal blood condition of pernicious anaemia. The illness can always be arrested by injections of B12 which is only needed in very small quantities. It is still not clear how B12 functions in the metabolic processes, but in order to begin to come to grips with this problem it is essential to know the structure in detail.
In 1956, after eight years' work, Mrs. Hodgkin and her collaborators had clarified the B12 structure. Never before had it been possible to determine the exact structure of so large a molecule, and the result has been seen as a triumph for X-ray crystallographic techniques. It was also, however, a triumph for Mrs. Hodgkin. It is certain that the goal would never have been reached at this stage without her skill and exceptional intuition.
There is reason to hope that the detailed knowledge of the B12 structure, revealed as a result of this work, will make it possible both to understand how this vitamin assists in the body's metabolism and to synthetize it. For the time being it has to be produced via bacterial fermentation.