For the first time, scientists have used machine learning to design brand new enzymes, which are proteins that speed up chemical reactions. This is an important step in the field of protein design as new enzymes could have many applications in medicine and industrial manufacturing.
“Living organisms are remarkable chemists. Rather than relying on toxic compounds or extreme heat, they use enzymes to break down or build up whatever they need under gentle conditions. New enzymes could put renewable chemicals and biofuels within reach,” said senior author David Baker, professor of biochemistry at the University of Washington School of Medicine and recipient of the 2021 Breakthrough Prize in Life Sciences.
As reported in the journal Nature on Feb. 22, a team from UW Medicine’s Institute of Protein Design developed machine learning algorithms capable of generating light-emitting enzymes called luciferases. Laboratory tests confirmed that the new enzymes can recognize specific chemicals and emit light very efficiently. This project was led by two postdocs at Baker Lab, Andy Hsien-Wei Yeh and Christoffer Norn.
The article in Nature is titled De novo design of luciferases using deep learning.
To make new luciferase enzymes, the team first selected chemicals called luciferins for the proteins to act on. They then used software to generate thousands of possible protein structures that could react with those chemicals.
During laboratory tests, the researchers identified an efficient enzyme called LuxSit (Let there be light). The enzyme carried out the desired chemical reaction. Refinement of the enzyme led to dramatic increases in performance. An optimized enzyme called LuxSit-i generated enough light to be visible to the naked eye. It has been found to be brighter than the natural luciferase enzyme found in the luminous sea pansy, Renilla reniformis.
“We were able to design very efficient enzymes from scratch on the computer instead of relying on enzymes found in nature. This breakthrough means that, in principle, custom enzymes could be developed for almost any chemical reaction,” Yeh said.
Biotechnology, medicine, environmental remediation and manufacturing could benefit from new enzymes. In biotechnology, for example, enzymes can improve biofuel production, food processing, and pharmaceutical manufacturing. In medicine, enzymes can serve as therapeutic and diagnostic tools. Enzyme design can improve the environment by breaking down pollutants or remediating contaminated sites. And enzymes can also help create new materials like biodegradable plastics and adhesives.
This research was led by scientists from the UW School of Medicine and included collaborators from the University of California, Los Angeles.
This work was supported by Howard Hughes Medical Institute, National Institutes of Health (K99EB031913), United World Antiviral Research Network, National Institute of Allergy and Infectious Disease (1 U01 AI151698-01), Audacious Project at the Institute for Protein Design, Open Philanthropy Project Improving Protein Design Fund, Novo Nordisk Foundation (NNF18OC0030446), National Science Foundation (CHE-1764328, OCI-1053575), and Eric and Wendy Schmidt on recommendation of the Schmidt Futures program. The National Natural Science Foundation of China (22103060) provided partial computing resources.