The article describes the computational design and experimental characterization of enzymes that catalyze the Kemp elimination reaction, a model for proton transfer from carbon. The authors used a combination of quantum mechanical transition state calculations and RosettaMatch hashing algorithm to design eight enzymes with two different catalytic motifs. These enzymes showed significant rate enhancements (up to 10^5) and multiple turnovers. Mutational analysis confirmed that catalysis depends on the computationally designed active sites, and high-resolution crystal structures validated the designs with atomic accuracy. In vitro evolution further improved the kcat/Km values by over 200-fold. The results demonstrate the power of combining computational protein design with directed evolution for creating new enzymes and suggest a wide range of potential applications in biotechnology, biomedicine, and industrial processes.The article describes the computational design and experimental characterization of enzymes that catalyze the Kemp elimination reaction, a model for proton transfer from carbon. The authors used a combination of quantum mechanical transition state calculations and RosettaMatch hashing algorithm to design eight enzymes with two different catalytic motifs. These enzymes showed significant rate enhancements (up to 10^5) and multiple turnovers. Mutational analysis confirmed that catalysis depends on the computationally designed active sites, and high-resolution crystal structures validated the designs with atomic accuracy. In vitro evolution further improved the kcat/Km values by over 200-fold. The results demonstrate the power of combining computational protein design with directed evolution for creating new enzymes and suggest a wide range of potential applications in biotechnology, biomedicine, and industrial processes.