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Correlating the work on penicillin


Mapping the molecular structure of penicillin
Dorothy Hodgkin Scientist
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I mean, what we were working on at that moment was just putting the... getting the system working. I mean, the... one had to have something representing atoms, so he [Charles Bunn] had, in fact, circles of different size, and... which he photographed through the fly's eye spread of pinholes. And he had to check up what size corresponded to what kind of atom. But he managed, he did most, all of that, and I just... standing near really at that particular time, and seeing the first trials go on, testing out the distribution of atoms with the... through the pinholes array to get an array of intensities which should correspond to the projection down the B-axis of the structure as a whole.

I didn't get very... we didn't get very far with it then, and I went back to Oxford for the next term, and he always supposed he shouldn't really work at it, because he was working at whatever ICI had told him to do during his working hours, and he would just work at penicillin in the evening, until, mercifully... what was his name?  The head of ICI altogether? Lord... I don't remember.

[Q] The head of ICI?

Wasn't Sir Robert Vantage it was his brother, wasn't it? Came in Monday, and he noticed some papers lying about with penicillin written on them, and said to Charles, the others being about in the room, listening, 'Oh, I am glad you are working on this'. And after that, when I came back, I found that penicillin was properly stamped on all the bits of relevant paper. Job number whatever-it-was, I forget.

[Q] So how long did it take to get to the final solution?

Well, there was a long hold-up during the summer, where nothing much was really reached or done, and I went, unfortunately, into this stupid situation, I became pregnant and had a miscarriage, and didn't work then, longer.

When I got back to Oxford, I found a letter from Charles asking, for a little more information about my first observations, and particularly the optics of the sodium salt, so I sent him these. And after that, he made a whole plan of what the molecule was like, and... and started moving it about over the area, and getting more different pinhole effects, until he found one that seemed quite good. And we in the meantime had done, essentially, the same for the potassium and sodium salts... the potassium and rubidium salts. We had found the heavy atom positions, calculated the sign contribution, which didn't give us signs for all the array, but about half of it. Then we calculated the electron density maps of the potassium and rubidium salts, which we knew must be imperfect, because there were some terms left out.

Then Charles sent me the electron density map, which he had reached by his trial and error operation, and I drew it out to the same scale as the other ones, and... well, I meant to bring it with me, but couldn't find, couldn't find it in time, the two sheets: you just put together, put one on top of the other and move them one over one another to find which bits hang together, because the arrangement of the molecules are different. That's quite quickly done, I used to make people do it in, through an afternoon visiting the lab. And then you immediately can see, from the sort of group that fits together and constitutes one molecule, where the phenyl group must be, and where the thiazolidine group must be, and in between, presumably the oxazolone ring or the beta-lactam ring. So at first we postulated an oxazolone ring and calculated the next highest intensities and found their signs. Mostly, what we did was, after not much in the way of calculations, we had these structure factor graphs drawn out, and we just put the map of the atomic positions over the top, and calculated extremely roughly 20, 10, so on, what we thought the contribution to the three of the new terms, and so we found how the signs were changing. Then we calculated a new map with perhaps just five extra terms in it, and immediately we began to see that the atoms which were given the oxazolone position moved the ring, broke open, and the atoms moved into the beta-lactam position.


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: Charles Bunn

Duration: 6 minutes, 38 seconds

Date story recorded: 1990

Date story went live: 02 October 2009