TOOLS FOR COMBINATORIAL MACROMOLECULAR CRYSTALLIZATION

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The importance of three-dimensional X-ray crystallographic structural information in biological research, ranging from the elucidation of enzyme mechanisms to anti-AIDS drug design, has led to the call for a massive effort in the scientific community to determine the structures of all the representative protein folds. In determining X-ray crystal structures, one of the most critical steps in growing crystals of the target molecule. Unfortunately, technological advancements in macromolecular crystallization have not kept pace with other areas of macromolecular X-ray crystallography. We propose the development, prototype production, and testing of novel high-density crystallization plates, and relational database software for collecting and organizing crystallization results data. These innovative products will incorporate the space, time, and effort-saving concepts of modern combinatorial chemistry into macromolecular crystallization. The development of these hardware and software tools will yield an integrated package designed to enable any molecular biology research to grow macromolecular crystals, the first step towards making X-ray crystallography a routine part of his or her research program. Such participation by researchers at all levels of molecular biology will be the scale of effort required for a project as ambitious as determining the three-dimensional structures of all the representative protein folds. PROPOSED COMMERCIAL APPLICATIONS: The proposed research has immense commercial value since it will integrate combinatorial chemistry and X-ray crystallography, two of the most powerful techniques in modern drug discovery. Success in Phase I will yield of user-yield research tools designed to be used "straight out of the box" to enable any molecular biology researcher, regardless of prior X-ray crystallography experience, to grow X-ray diffraction quality crystals of their target biomolecules. Furthermore, these Phase I studies will allow us to proceed toward our long-term goal of completely automating the crystallization of biological macromolecules for large scale projects requiring high-throughput crystallization screening. The development of such technology would form the basis for numerous products and patents, such as automated crystallization robots. The ever-growing market for the products developed under this proposal is very large, as it includes all macromolecular X-ray crystallography and molecular biology researchers in academia, as well as industry.