De novo enzymes: from computational design to mRNA display

Enzymes offer cheap, environmentally responsible and highly efficient alternatives to chemical catalysts. The past two decades have seen a significant rise in the use of enzymes in industrial settings. Although many natural enzymes have been modified through protein engineering to better suit practical applications, these approaches are often insufficient. A key goal of enzyme engineers is to build enzymes de novo – or, ‘from scratch’. To date, several technologies have been developed to achieve this goal: namely, computational design, catalytic antibodies and mRNA display. These methods rely on different principles, trading off rational protein design against an entirely combinatorial approach of directed evolution of vast protein libraries. The aim of this article is to review and compare these methods and their potential for generating truly de novo biocatalysts.