A new AI-based program, dubbed Raygun, can suggest strategic cuts to a protein’s amino acid sequence to shrink the overall structure without affecting the protein’s function (Nature 2026, DOI: 10.1038/s41586-026-10842-8).
The tool shrank fluorescent proteins EGFP and mCherry by 10–15%, and the resulting proteins still glowed under excitation.
For example, miniaturizing fluorescent proteins that act as tags to image biological processes and tissues could make them less obtrusive and less likely to interfere with the thing they’re tagging, Singh says.
Advertisement“De novo design is about creating something in an entirely new part of the protein space.
While this may seem counterintuitive, expanding a protein’s size could be helpful if researchers want to add a new domain to an existing protein.
A new AI-based program, dubbed Raygun, can suggest strategic cuts to a protein’s amino acid sequence to shrink the overall structure without affecting the protein’s function (Nature 2026, DOI: 10.1038/s41586-026-10842-8). The tool shrank fluorescent proteins EGFP and mCherry by 10–15%, and the resulting proteins still glowed under excitation.
“This is an approach that essentially reasons from evolutionary patterns in protein sequences to figure out what the critical pieces are,” says Rohit Singh, a computational biologist at Duke University who led the work in collaboration with his colleague Scott Soderling. “You can ask for much more extensive substitutions than you would typically have by point-by-point mutations.”
Shrinking proteins could potentially make them easier to use. For example, miniaturizing fluorescent proteins that act as tags to image biological processes and tissues could make them less obtrusive and less likely to interfere with the thing they’re tagging, Singh says. Or shrinking sequences could help address one of the main issues with gene therapy: the limited capacities of delivery vehicles like adeno-associated viruses, he adds.
While the Raygun approach may be compared with designing proteins from scratch, Singh says these techniques aren’t necessarily competitors and could even be used in tandem.
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“De novo design is about creating something in an entirely new part of the protein space. Raygun is about exploring the space around it more effectively,” he says. “So you could actually make a de novo design and then still apply Raygun on top of it to then explore the space around that specific novel design.”
The tool has another interesting possibility—the ability to expand proteins as well as shrink them. While this may seem counterintuitive, expanding a protein’s size could be helpful if researchers want to add a new domain to an existing protein. Singh says they are still developing this utility for the algorithm.
