On July 12th the British Crystallographic Association organised a meeting at the Royal Society, to mark the publication of Dorothy Hodgkin's collected papers by the Indian Academy of Science. The meeting was initiated and planned by Sivaraj Ramaseshan, Judith Howard and Guy Dodson to provide an opportunity to review the current state of research areas where Dorothy had made major and often the first contributions. The topics of discussion were cholesterol, penicillin, Vitamin B12, proteins (specifically pepsin-related enzymes and insulin), as well as current and future developments in crystallography. The papers span her scientific career from 1935 to 1989, their importance lies in their crystallographic skill and originality and because they helped to change the way that chemists thought and because they signalled the importance of structural knowledge to both chemistry and biology.
Lord Phillips of Ellesmere, better known to the community as David, delivered the opening remarks, identifying Dorothy's particular influence on the crystallographic careers of most of the speakers, and also many of the audience. He used the quotation from A Midsummers Nights Dream to illustrate the scientific imagination many had felt Dorothy was capable of:
The poet's eye, in a fine frenzy rolling,
Doth glance from heaven to earth, from earth to heaven;
And, as imagination bodies forth,
The forms of things unknown, the poet's pen
Turns them to shapes, and gives to airy nothing
A local habitation and a name.
The first session, on cholesterol, was opened by David Blow. He surveyed the early studies by Crowfoot and Bernal of sterol crystals. They had extracted a great deal of information about possible structures from knowledge of the chemical composition, and the unit cell. He pointed out that the early conflicts over the form of the steroids, reported in the Journals of 1933, would have been well- known to Dorothy, and were in acute contrast to her own approach to scientific discussion and publication. The recent extensive research on the chemistry of the steroid- binding enzymes was described by David Blow and Bill Duax, the second speaker. The displacement of water molecules from the binding site of cholesterol oxidase was analysed in detail by David Blow while Bill Duax presented a lively account of the specificity of short-chain dehydrogenases and the effect of liquorice on blood pressure.
The penicillin session was devoted entirely to discussion of the crystal structure of isopenicillin N synthase determined in Oxford. (This work carries on the tradition of Oxford chemistry; Chaim, Abrahams and Dorothy were all involved in early work on antibiotics.) Peter Roach demonstrated how the knowledge of the structure allows an understanding of the details of the extraordinary chemistry by which the beta lactam and thiol rings are closed during the synthetic reaction.
The exciting new structure of methylmalonyl CoA-mutase was described by Phil Evans. It requires the co-factor adenosyl-cobalamin and generates a free radical in its mechanism of action. It was shown that there is a large conformational change on binding of this cofactor, and as a result the benzimidazole is replaced by a histidine from the enzyme. Jenny Glusker's talk approached the structure from a different viewpoint. She described attempts to model the conformational variability of the enzyme, and presented some ab initio molecular orbital data on the free radical rearrangement that occurs in methionine synthase, another B12 utilising enzyme. A lively discussion was triggered by these two complementary presentations.
The protein session reflected Dorothy's deep interest in proteins and her recognition of their importance to biochemistry and medical science. The complexity of protein molecules obviously presented huge crystallographic problems (insoluble at the time), which however did not deter Dorothy from their study. In 1934 Dorothy and J D Bernal reported in Nature the first X-ray diffraction pattern obtained from a protein, pepsin. They predicted " ...... now that a crystalline protein has been made to give X-ray photographs, it is clear that we have the means of checking them and, by examining the structure of all crystalline proteins, arriving at far more detailed conclusions about protein structure than previous physical or chemical methods have been able to give".
Tom Blundell looked at the aspartic proteinase family whose members are present in a wide variety of organisms and some of which most notably HIV protease and renin, are targets for structure-based drug design.
When Dorothy went to Oxford she began research into insulin's structure a commitment for the rest of her working life. The structure determination of insulin has led directly to the design of mutant insulins now being used in diabetic therapy. and in his presentation Guy Dodson went on to discuss how structural knowledge is being applied to the phenomenon of insulin fibril formation.
The final session was of general interest. Jack Dunitz gave an overview of what crystallography has contributed to chemistry, biochemistry, and physics. He pointed out something implicit in the discussion after the B12 papers viz. crystallographers prefer molecules to be stable, whereas chemists are most interested in molecules as part of a reaction process. The chemical approach can be based on the comprehensive and accessible data bases now available
Michael Rossmann summarised the state of play in the macromolecular field. He foresees the subject becoming increasingly rigorous and more and more being driven by the molecular biologists with structural analyses becoming one weapon in the armoury for attacking biological questions.
Finally Max Perutz was asked to comment on the challenges facing scientists in the 1930s compared to those of the 1990s struggling to understand the immense complexity of molecular biology. Interestingly he felt (with hindsight!) that the problems he and Dorothy faced were simpler - they knew that if they had better techniques their problems could be solved, whereas now more knowledge is not leading to simplification, if anything the reverse.
Many of those who had worked with Dorothy in Oxford stayed on for a most enjoyable dinner at which Siv Ramasechan reminisced about Dorothy's influence and travels in India.
Eleanor Dodson
University of York
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