Chapter 4: Computational Enzyme Design: Successes, Challenges, and Future Directions

The development of a broadly-applicable computational method for the design of enzymes that can catalyze any chemical reaction with high efficiency and selectivity under defined conditions is a major objective of protein designers. Over the past two decades, significant progress towards this goal has been achieved through the development of computational enzyme design technologies, which have opened the door to the creation of de novo enzymes capable of catalyzing a variety of bond-breaking and bond-forming reactions. Even so, continued development of these methodologies is essential to realize the design of enzymes displaying catalytic efficiencies equal to those of natural biocatalysts. Here, we present an overview of computational enzyme design protocols, review examples of their application towards the design of de novo enzymes that can perform predefined organic transformations, discuss current limitations of the technology, and provide possible ways forward to address these challenges.