An evolution-based model for designing chorismate mutase enzymes

William P. Russ, Matteo Figliuzzi, Christian Stocker, Pierre Barrat-Charlaix, Michael Socolich, Peter Kast, Donald Hilvert, Remi Monasson, Simona Cocco, Martin Weigt, Rama Ranganathan

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)440-445
Number of pages6
JournalScience
Volume369
Issue number6502
DOIs
StatePublished - Jul 24 2020

ASJC Scopus subject areas

  • General

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