GOOSE: Understanding and Designing Intrinsically Disordered Protein

We often read papers about the three-dimensional (3D) structures of proteins, particularly as rapidly evolving technologies such as cryo-EM, increasingly aided by AI, allow us to explore increasingly complex protein structures. However, not all proteins—or all regions within a protein—adopt a stable 3D structure.

Some proteins, or specific regions of proteins, remain intrinsically disordered. These intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) are not simply “unstructured” or non-functional. They play important roles in many cellular processes, including molecular recognition, signaling, regulation, and protein assembly.

What Determines Protein Folding?

One important factor is the balance between hydrophobic and hydrophilic amino acids in a protein. Both are essential for protein folding and function. Hydrophobicity is the driving force for protein folding. Hydrophobic residues tend to avoid exposure to water, initiating the folding process and clustering together to form a compact hydrophobic core inside the protein, eventually being buried within the protein. In contrast, hydrophilic and charged residues interact favorably with water and are more frequently exposed on the protein surface, surrounded by water molecules.

Folded proteins generally have sufficient hydrophobicity to drive compaction and formation of a hydrophobic core. In contrast, IDPs/IDRs generally have lower mean hydrophobicity and higher proportions of polar and charged residues. Too much hydrophobicity can lead to aggregation. A well-balanced distribution of hydrophobic and hydrophilic residues is an important determinant of 3D protein structure.

GOOSE: A Computational Framework for IDR Design

While computational design of folded proteins has advanced rapidly, designing functional IDRs remains much more challenging. This is where GOOSE (Generate disOrdered prOteins Specifying propErties) becomes particularly interesting. GOOSE is a computational framework developed specifically for the rational design of intrinsically disordered proteins and regions. Rather than designing a sequence to produce one defined 3D structure, GOOSE enables researchers to design sequences with specified physicochemical properties and desired disordered-state behaviors.

Using GOOSE, the researchers demonstrated several interesting applications:

• Controlling structural ensembles in cells — designing IDRs with specific conformational behaviors inside living cells.
• Responding to cellular changes — designing IDRs that respond to structural changes associated with decreased cell volume.
• Building functional scaffolds — designing IDRs that self-assemble and selectively recruit specific protein clients.
• Protecting cells from desiccation — designing novel IDRs that help protect cells under drying conditions.

A major advantage of GOOSE is its high-throughput design capability. Researchers can generate and experimentally test thousands of IDR sequences, making it possible to systematically uncover sequence-to-property and sequence-to-function relationships that would be difficult to identify through conventional trial-and-error approaches. This makes GOOSE not only a tool for designing new functional IDRs, but also a powerful platform for understanding how sequence composition and physicochemical properties control protein disorder, dynamics, assembly, and function.

Read more:

Rational design of disordered proteins for sequence–function investigation, Nature (2026).

DOI: 10.1038/s41586-026-10849-1. www.nature.com/articles/s41586-026-10849-1