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Protein Cristallisation

Protein crystallization seeks to determine the structures of proteins by passing X-ray energy through protein crystals and examining the diffraction pattern. In basic biological research, protein structures provide insight into the mechanism and function of a protein. In pharmaceutical research, protein structure is important to help the medicinal chemist design drug molecules that will effectively interact with the target protein, a protein that is related to a disease. This process involves the use of computer simulations to "dock" the drug molecule to the three-dimensional shape of the protein’s active site, similar to trying to different keys in a lock to see which fits the best. From these computer simulations, the chemist can synthesize molecules, which have a better probability of finding an effective drug compound.

In the past, protein crystallography has been a labor-intensive, low-throughput process. Many times during a drug project, the protein crystal structure would be discovered but the project would be too far along to use the information. Further, in the early late 1980’s, protein crystallography was to have made finding a blockbuster drug as simple as docking the right molecule, synthesizing it, and taking it to the clinic. However, these "designer drugs" failed to pan out in the clinic.

The sequencing of the human genome project has produced the fields of genomics and proteomics, global study of an organisms genes and protein, respectively. Knowing all the genes and proteins of an organism has led to the desire to know the structure of all the proteins of an organism (hundreds of thousands). Consequently, the field of "structural genomics" has emerged which uses high throughput protein crystallography as its central platform to solve the structure for thousands of proteins.

High-throughput protein crystallography involves using many of the automation concepts from High Throughput Screening (HTS). The liquid handling requirements are similar to those for HTS:

  • Low volume - traditional crystallography plates have 24 or 48 wells with well volumes of 100s of microliters. For higher throughput, the number of wells has increased to 96 or 384. As a result, the reservoir and drop volumes have significantly decreased. A dispenser must be able to accurately and reproducibly dispense in this low volume range.
  • High Speed - with lower volumes, the dispensing operation must be rapid to prevent evaporation, which can change the concentration of the mother liquor.
  • Mixing - when the protein is added to the drop of mother liquor, effective mixing must occur. For a drop of 1 µL, this can be difficult.
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