The ability to construct, at will, """"""""artificial"""""""" enzymes for which no natural counterparts exist, would have a profound effect on chemical synthesis. For such artificial enzymes could be employed to selectively catalyze many reactions that are presently either chemically or economically infeasible. In the long-term, these synthetic catalysts may also contribute to the pharmacopeia of human medicine, being used not only in production of new pharmaceuticals, but also (perhaps in micro- encapsulated form) for directly treating a variety of illnesses - illnesses resulting from a sufferer's inability to (i) properly process biological precursors or (ii) metabolize/excrete by-products or toxins. The objective of this project is to construct two fully synthetic active sites (1/1') designed to catalyze bond formation. Each active site, which is an organic molecule with a molecular weight < 1,000, contains substrate binding sites and a catalytic unit and is intended to exhibit catalysis, selectivity, and turnover. The two active sites will employe transition state stabilization to achieve their catalytic activity. The synthesis of 1/1', which takes advantage of the commercial availability of large subunits, should afford 1/1' by a highly convergent route in which the longest synthetic sequence is little more than a dozen steps in length. Synthetases 1/1' are intended to operate in organic solvents, because they use hydrogen bonding for recognition and binding. Alternatives to 1/1' are also described to allow for the possibility that unexpected difficulties with 1/1' may surface. The proposal outlines the strategies reflected in the design of 1/1' and details how individual elements in the concept of 1/1' (including substrate binding, transition state stabilization, proton transfer, flexibility vs. rigidity, product release, turnover and selectivity) will be incorporated, measured and optimized. For the ultimate goal is to demonstrate that the design concepts are general in nature, and can be easily applied to the solution of a virtually unlimited array of synthetic and other practical problems.
