Scientists design proteins that can change their shapes

In a new move, researchers have shown that protein design software can incorporate motion into its outputs. The resulting protein gives a wave with one arm as it binds and releases a calcium ion (Science 2025, DOI: 10.1126/science.adr7094).

The work builds on advances in protein design with deep learning, including the ability to predict a protein structure from a sequence and vice versa, especially as computing power has increased.

To make the new flexible fold, Amy Guo, a doctoral student in Tanja Kortemme’s group at the University of California, San Francisco, took a naturally occurring, static calcium-binding protein and programmed in the movement by focusing on a secondary helix structure. Guo introduced changes to the protein that would give it two conformations: one state where it would bind the calcium and one state where it would “destabilize its calcium binding site”—essentially letting go of the calcium.

While Nobel prize–winning AI-powered protein design has come a long way, “what these algorithms optimize is to make the structure extremely stable. And so that means that they now have one very defined, very stable structure,” Kortemme says. Designing “dynamic” proteins, or proteins that can move, is much harder because a designer must come up with a structure that doesn’t just work in one position but multiple, and the protein has to be able to transition between the positions.

“Previous work has led to the design of proteins where whole domains re-orient. Other approaches have shown that it’s possible to design metamorphic proteins, where an entire domain can shape-shift,” says John Orban, a professor at the University of Maryland’s Institute for Bioscience and Biotechnology Research and who was not involved in the work, in an email to C&EN. “This new work falls somewhere in between, now adding the ability to design proteins with intra-domain re-orientations of secondary structure elements.”

Kortemme hopes to use these advances to create new proteins that can be precisely controlled. She is especially interested in creating completely new “protein machines” that can change their shape in response to an energy input.