An evolution-based model for designing chorismate mutase enzymes

The rational design of enzymes is an important goal for both fundamental and practical reasons. Here, we describe a process to learn the constraints for specifying proteins purely from evolutionary sequence data, design and build libraries of synthetic genes, and test them for activity in vivo using...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) Vol. 369; no. 6502; p. 440
Main Authors: Russ, William P, Figliuzzi, Matteo, Stocker, Christian, Barrat-Charlaix, Pierre, Socolich, Michael, Kast, Peter, Hilvert, Donald, Monasson, Remi, Cocco, Simona, Weigt, Martin, Ranganathan, Rama
Format: Journal Article
Language:English
Published: United States 24.07.2020
Subjects:
Amino Acid Sequence
Chorismate Mutase - chemistry
Chorismate Mutase - genetics
Escherichia coli Proteins - chemistry
Escherichia coli Proteins - genetics
Evolution, Molecular
Models, Genetic
Models, Statistical
ISSN:1095-9203, 1095-9203
Online Access:Get more information
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Summary:The rational design of enzymes is an important goal for both fundamental and practical reasons. Here, we describe a process to learn the constraints for specifying proteins purely from evolutionary sequence data, design and build libraries of synthetic genes, and test them for activity in vivo using a quantitative complementation assay. For chorismate mutase, a key enzyme in the biosynthesis of aromatic amino acids, we demonstrate the design of natural-like catalytic function with substantial sequence diversity. Further optimization focuses the generative model toward function in a specific genomic context. The data show that sequence-based statistical models suffice to specify proteins and provide access to an enormous space of functional sequences. This result provides a foundation for a general process for evolution-based design of artificial proteins.
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ISSN:1095-9203
1095-9203
DOI:10.1126/science.aba3304