Catalytic efficiency of designed catalytic proteins

•De novo designed catalysts still are barely matching catalytic efficiency of small molecules.•Best design strategies focus on the active site functional tuning and protein stability.•Computationally designed catalysts can be (and need be!) further improved by directed evolution.•All parts of the catalytic cycle need to be considered for a successful design. The de novo design of catalysts that mimic the affinity and specificity of natural enzymes remains one of the Holy Grails of chemistry. Despite decades of concerted effort we are still unable to design catalysts as efficient as enzymes. Here we critically evaluate approaches to (re)design of novel catalytic function in proteins using two test cases: Kemp elimination and ester hydrolysis. We show that the degree of success thus far has been modest when the rate enhancements seen for the designed proteins are compared with the rate enhancements by small molecule catalysts in solvents with properties similar to the active site. Nevertheless, there are reasons for optimism: the design methods are ever improving and the resulting catalyst can be efficiently improved using directed evolution.