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Structural Biochemistry/Dorothy Crowfoot Hodgkin

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Pepsin

Dorothy Crowfoot Hodgkin (1910–1994) is credited with being the founder of protein crystallography. In addition to further developing and refining the technique of X-ray crystallography, she determined the three dimensional structures of pepsin, cholesterol, lactoglobulin, ferritin, tobacco mosaic virus, penicillin, vitamin B-12, and insulin, among many others. She was the first person to discover the shape of a globular protein (pepsin), and she won the 1964 Nobel Prize in Chemistry for determining the molecular shape of hundreds of molecules.

Dorothy Crowfoot graduated from Somerville College of Oxford in 1932 with a degree in chemistry. She began her doctoral work at Cambridge in 1933 with Dr. J.D. Bernal, where she first studied the structural arrangement in atoms of crystals. Realizing that she could use X-ray crystallography to study more complex molecules, she determined that proteins should be studied with the “mother” matrix surrounding them and not air dried, as was standard procedure at the time.

Cholesterol

Further improvements she devised for the technique of X-ray crystallography occurred during her study of cholesterol iodide and over one hundred other steroids. Her accomplishments include the reporting of unit-cell dimensions, recording of reactive indices with respect to their crystallographic axes, which showed the molecules crystal packing, and the elucidation of the hydrogen-bond scheme among atoms. These techniques were a major breakthrough for legitimizing X-ray crystallography as an accurate analytical technique because her analyses were the first that were based on three dimensional calculations and that established the stereochemistry at each carbon atom.

Penicillin core

In 1934 she returned to Oxford on a research fellowship, where she crystallized and X-ray photographed insulin. To determine its structure, she worked with an isomorphous crystal, a derivative molecule where a single atom is replaced by a heavier one. Thirty four years later, she would finally find success in determining the structure of insulin. Meanwhile, she received her doctorate from Cambridge University and married Thomas Hodgkin in 1937 and began her work on determining the structure of penicillin. She determined that there were three derivatives of benzylpenicillin, sodium, potassium, and rubidium. She used the techniques of isomorphous replacement, optical analogs, and difference maps to elucidate the structure. She also used the first IBM analog computers to do the X-ray calculations, which was the first use of an electronic computer to solve a biochemical problem. Penicillin was instrumental in treating wounded soldiers during World War II, and saved many lives. Knowing penicillin's structure enabled the synthesis of chemically modified penicillin, crucial for the high demand encountered during the war. While completing her penicillin research, Dr. Hodgkin was named a fellow of the Royal Society, Britain's premiere scientific organization, in 1947.

VitaminB12

From 1955 to 1961 she worked on determining the structure of vitamin B-12 by locating the positions of the heavy atoms, using direct Patterson methods, and then calculating the three-dimensional Fourier series using observed F values and phases based only on the heavy atom's positions. By pioneering the use of Patterson maps, Dorothy was able to approximate the correct electron density series.

In addition to receiving the Royal Medal, she also won a Nobel Prize in Chemistry 1964, making her the third woman to win the Nobel. She was named by Queen Elizabeth II as a member of the Order of Merit, the United Kingdom's highest royal order, in 1965.

Without Dorothy Crowfoot Hodgkin's pioneering techniques and contributions to structural biochemistry, it is doubtless that the field would not be as advanced as it is today.

References

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