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The Claisen rearrangement of chorismate to prephenate has become an important model system for developing understanding of enzymatic catalysis as well as for computational treatment of enzyme active sites. This thesis presents general methods for the computational design of enzyme active sites and applies these methods to the design of catalysts for the chorismate-prephenate rearrangement. The computational methods described allow the incorporation of transition-state structures and other small molecules into protein design calculations. These design procedures were tested through redesign of the active site of Escherichia coli chorismate mutase. The six predicted mutations were experimentally characterized and most maintained or increased the catalytic activity of the enzyme. To further investigate the context of the mutations predicted in the calculation and the tolerance of a natural enzyme to secondary active site mutations, extensive substitution experiments were performed. The effect of every amino acid in five active site hydrophobic positions and one N-capping position was evaluated. These experiments clarified some of the strengths and weaknesses of the computational modeling procedure. Finally, attempts to design a completely new enzyme for catalysis of the chorismate-prephenate rearrangement are discussed.