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The phase problem


Complex chemistry
Dorothy Hodgkin Scientist
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Again it was quite difficult for everyone to take this different unit with two rings...

[Q] Yes, chemically challenged.

... together.  But we just... with Ken's group in collaboration, then went straight on from there from the 26 atom map. You could see smaller peaks corresponding to the atoms that were left out of the electron density and when we put these in as atoms, they really were practically the whole molecule and the thing was at this stage a rather amusing episode occurred all of which is written up by Ken in my festschrift. That's to say, I first of all just expected him to send this great mass of computing over by sea and it took several weeks, and when I saw what was happening to it I thought, God, how silly to waste all this money just waiting for this to come in by sea, and I sent a telegram saying send everything airmail. And then Ken got a feeling that we were terribly slow at choosing which atoms we should put into the phasing operation and he would just take all of them below that he could see, above a certain level and so he sent a map that was based I think... anyway the numbers are all in the paper, on 60 odd atomic positions. Now we could see that some of these positions were absolutely wrong and hopeless, and one was a peak in the middle of a ring you see and chemically it wouldn't make sense at all, and we only put in 54 atoms which we regarded as all chemically desirable atoms. And then there was a little sort of wrangle about... between us as to which atoms were real and which were just...

[Q] Artifactual.


[Q] But the calculations did discriminate quite successfully?

Yes. Quite successfully and so we came through with a complete structure all right.

[Q] Which then in a sense moved into the world of chemistry because they had to decide, chemically, how to attack this problem, if I'm right? They had the question of synthesising that wasn't there?

Ah yes. At that... yes. That's years of work.

[Q] I mean it was an important development it seems to me, because here was a structure which was unanticipated and yet the chemists needed to synthesise and they had to think very hard how to do it?

Oh yes, well this was Bob Woodward's main ploy but it was Bob Woodward's combined with Eschenmoser, and Eschenmoser did the first synthesis of the corrin nucleus. But of course he synthesised it as the nickel corrin and not as cobalt corrin and he hadn't got anything natural to do mixed melting points or anything like that, so how he was sure that he had calculated... that he had really got a corrin in his synthetic preparation was by doing an X-ray analysis of it and...

[Q] Yes. Well at that stage it must have been the most powerful way of working on complex chemistry at that...

Yes, but not even crystallographers realised this you know.

[Q] No, that is true.

Bragg didn't realise that that was what this thing was. He published it in his last little book as the sort of final map of B12 or something like that he had, and I had to write to David Phillips and point out this was not at all the case.


British pioneer of X-ray crystallography, Dorothy Hodgkin (1910-1994), is best known for her ground-breaking discovery of the structures of penicillin, insulin and vitamin B12. At age 18, she started studying chemistry at Somerville College, Oxford, then one of the University of Oxford colleges for women only. She also studied at the University of Cambridge under John Desmond Bernal, where she became aware of the potential of X-ray crystallography to determine the structure of proteins. Together with Sydney Brenner, Jack Dunitz, Leslie Orgel, and Beryl Oughton, she was one of the first people in April 1953 to see the model of the structure of DNA, constructed by Francis Crick and James Watson. She was awarded the 1964 Nobel Prize in Chemistry and is also known for her peace work with organisations such as Science for Peace and the Medical Aid Committee for Vietnam. All recorded material copyright of The Biochemical Society.

Listeners: Guy Dodson

Guy Dodson studied chemistry and physical science at the University of New Zealand, followed by a PhD on the crystallographic study of an alkaloid. In 1961, he came to Oxford to work on the crystal structure of insulin. In the mid 1970s Guy and his wife moved to York University to establish a laboratory. In addition to insulin studies the laboratory has investigated many complex molecules of medical significance, including haemoglobin, myoglobin, HIV related proteins, proteases and proteins involved in managing nucleic acids in cells. In 1993, he went to the NIMR in London to establish a crystallographic group in an environment that spanned molecular, physiological and disease-related disciplines. Here his research began on some cell signalling proteins. His interests on medically relevant proteins included prions, malarial and TB proteins, and some clinically relevant thrombin inhibitors. Guy Dodson retired in 2004 but is still finding much to do in York and the NIMR.

Tags: Ken Trueblood

Duration: 4 minutes, 43 seconds

Date story recorded: 1990

Date story went live: 02 June 2008