A quick introduction into protein X-ray crystallography:

What information do we get from X-ray crystallography?

Proteins, which are the machines inside our cells that use energy to do countless tasks, such as copy our DNA for the next cell, cause our muscles to contract, bind hormones, allow our neurons to release hormones and neurotransmitters. It is vastly helpful to understand what proteins look like, their 3-dimensional structure, to understand how they work. For example, take the protein, DNA helicase. In order for our genome to be passed on to newly-divided cells or our progeny (in the form of sperm and egg cells), it must be copied. In order to be copied, it must be temporarily pulled apart from its more stable double-stranded form, to a single stranded-form where the information is accessible. DNA helicase is a motor that uses energy from ATP to unwind the DNA. In the image below, you can see that the structure of one molecule of the protein, which alone doesn’t really explain its function. But the protein binds five other identical helicase molecules to form a donut-shape, which encircles one strand of the DNA. The motor then drives the helicase forward, pulling the two strands apart by shear force.

 

 (PDB code: 2R5U) (http://www.pdb.org/pdb/explore/explore.do?structureId=2R5U)

This crystal structure is specifically of the helicase protein from the tuberculosis bacteria. Knowing the structure allows scientists to design drugs that bind the protein in the bacteria, but not in humans, and to prevent the bacteria from replicating.

How do we get this information?

Proteins are extremely small, too small to see with the human eye and the structure is too small to see with a microscope. But if we can get the protein to crystallize, forming a regularly repeating structure that is much bigger than the single protein alone, we amplify the signal-to-noise ratio. X-rays are then shot at the crystal. When the X-rays hit the atoms that make up the protein, they are diffracted, that is, the direction and intensity change. The pattern of diffraction provides information about the position of the atoms in the protein and the diffraction pattern is captured by a special camera device behind the protein. Of course, back when Dorothy Hodgkin was solving the structures of penicillin and Vitamin B12, there was no camera, the diffraction pattern was recorded on X-ray film. Using mathematical formulas, we can then backtrack to the structure, but there is a big caveat; some information, the phases, are missing from the diffraction pattern. There are several ways, which I won’t go into here, for crystallographers to get the missing information and solve the structure.

Dorothy Hodgkin contributed to the methods available to get this missing information and solve the phase problem. This included using selenium derivatives and using microorganisms to incorporate the selenium into the protein.