A new computational tool can design disordered proteins and decipher their function. The work could help scientists unravel the mysterious sequence–function relationship of intrinsically disordered protein regions, which exist in 70% of human proteins and are thought to have critical roles in the body, including disease.
Traditional protein design, a technique that won the chemistry Nobel prize two years ago, relies on the fact that proteins fold into fixed 3D shapes due to their sequence of amino acid building blocks. In turn, their fixed shape governs their function. But intrinsically disordered regions defy this rule. Instead, they continuously shape shift into unpredictable, unfixed structures, making them difficult to design and study with conventional techniques.
Now, US researchers have overcome this with a versatile computational system called Goose (Generate disOrdered prOteins Specifying propErties), which rapidly generates thousands of new disordered protein regions per minute that can be tested in cells to reveal distinct sequence-to-function relationships.
‘The ability to design disordered proteins at a large scale with our platform now allows us to learn how their component sequences affect the cell,’ says project co-leader Ryan Emenecker at Washington University in St Louis, US. ‘It gives us a lens through which we can learn how naturally occurring changes in these proteins might drive diseases like cancer.’
To develop Goose, the researchers built a vast library amino-acid sequences that are associated with specific cell functions. By requesting specified properties – including charge, hydrophobicity, sequence length and predicted interactions – machine learning was used to generate thousands of new disordered region sequences within seconds. These could then be tested for function in genetically engineered cells.
‘We can now map the way amino acids are arranged in intrinsically disordered proteins to their function,’ says Shahar Sukenik at Syracuse University, US, another co-leader of the project. To test Goose, the team designed and synthesised novel disordered proteins that could self-assemble inside cells, sense changes in their environment, and protect yeast cells from dehydration, some working better than natural proteins.
‘This opens the possibility of being able to make new sensors that are sensitive to things outside what natural sequences would be attuned to, like toxins or cell damage,’ Emenecker says. ‘It has the potential to be very valuable.’
‘The key advance is making disorder experimentally programmable,’ comments Kejia Wu, who investigates intrinsically disordered proteins in 2024 Nobel laureate David Baker‘s lab at the University of Washington in Seattle, US. ’The paper therefore treats disorder not as a problem to overcome, but as a design variable.’
Wu says the live-cell results are ‘particularly informative’ because some of the disordered proteins behaved unexpectedly beyond sequence information, possibly because of interactions with RNA or other cellular components, she suggests. ‘This emphasises that an intrinsically disordered region’s behaviour is determined not only by its sequence, but also by its partners, localisation and cellular environment.’
‘The study remains a proof of principle rather than a general solution to predicting IDR function, adds Wu. ’I see Goose as an enabling experimental platform rather than a finished predictive theory. I look forward to seeing how this advances.’
References
K Hunter et al, Nature, 2026, DOI: 10.1038/s41586-026-10849-1
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