Abstract
Recent years have seen an explosion of interest in understanding the physicochemical parameters that shape enzyme evolution, as well as substantial advances in computational enzyme design. This review discusses three areas where evolutionary information can be used as part of the design process: (i) using ancestral sequence reconstruction (ASR) to generate new starting points for enzyme design efforts; (ii) learning from how nature uses conformational dynamics in enzyme evolution to mimic this process in silico; and (iii) modular design of enzymes from smaller fragments, again mimicking the process by which nature appears to create new protein folds. Using showcase examples, we highlight the importance of incorporating evolutionary information to continue to push forward the boundaries of enzyme design studies.
Highlights
Conformational dynamics in enzyme design is crucial in increasing the sampling of states with new catalytic functions as well as reducing the sampling of nonproductive conformations
There has been significant progress in computational design studies based on evolutionary information, in particular due to increasing awareness of the role of conformational dynamics in the natural evolution of enzymes [12,14,15,16,17,18], which is being increasingly incorporated into the computational design process [15,17]
We discuss three directions where evolutionary information is being used to guide the computational design process, : (i) repurposing of protein scaffolds identified through ancestral sequence reconstruction (ASR) as potential starting points for the generation of new enzyme activities; (ii) harnessing conformational dynamics, a key driver of natural enzyme evolution, in computational enzyme design; and (iii) modular design processes based on identifying evolutionarily important subdomain segments that can be rearranged to create new enzymes
Summary
We discuss three directions where evolutionary information is being used to guide the computational design process, : (i) repurposing of protein scaffolds identified through ASR as potential starting points for the generation of new enzyme activities; (ii) harnessing conformational dynamics, a key driver of natural enzyme evolution, in computational enzyme design; and (iii) modular design processes based on identifying evolutionarily important subdomain segments that can be rearranged to create new enzymes. There have been a great number of experimental studies using ancestrally reconstructed proteins for enzyme design due to their greater thermostability; more recently, interest has shifted to using ASR to obtain scaffolds that can be used as starting points for the engineering of catalytic properties [22,23,27,31]. Electronic repository containing molecular and biochemical information on enzymes https://silviaosuna.wordpress.com/ tools https://www.brenda-enzymes.org
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