Understanding enzyme function evolution from a computational perspective

•Enzymes evolve new functionality through creeping or leaping modes of evolution.•Evolutionary step size can be quantified from changes in reaction and structure.•The observed evolutionary steps in a domain can inform de novo enzyme design.•Domain structure, dynamics and promiscuity can inform domain evolvability.

In this review, we will explore recent computational approaches to understand enzyme evolution from the perspective of protein structure, dynamics and promiscuity. We will present quantitative methods to measure the size of evolutionary steps within a structural domain, allowing the correlation between change in substrate and domain structure to be assessed, and giving insights into the evolvability of different domains in terms of the number, types and sizes of evolutionary steps observed. These approaches will help to understand the evolution of new catalytic and non-catalytic functionality in response to environmental demands, showing potential to guide de novoenzyme design and directed evolution experiments.