Rational design of disordered proteins for sequence–function investigation

Intrinsically disordered protein regions (IDRs) are ubiquitous across all kingdoms of life and have essential cellular roles. Despite their importance, the rational design of IDRs remains more limited compared to the substantial progress made in designing folded proteins. A comprehensive computational framework, GOOSE (Generate disOrdered prOteins Specifying propErties), has been developed to address this limitation. GOOSE's versatility and throughput enable the design and testing of thousands of IDR sequences to reveal distinct sequence-to-function relationships. By leveraging GOOSE, researchers can explore how sequence properties influence IDR structural ensembles in cells, design IDRs that respond to structural changes associated with cell volume decrease, create scaffold IDRs that self-assemble and recruit specific clients, and design novel IDRs that protect cells from desiccation. The authors' work demonstrates the power of rational sequence design in exploring function in IDRs and provides a versatile tool for designing functional disordered proteins. The GOOSE framework has the potential to accelerate the discovery of novel IDR functions and improve our understanding of the complex relationships between sequence and function in IDRs. However, it is essential to note that the design and testing of peptides using GOOSE is for research-use only and should not be used for therapeutic or clinical applications without further evaluation and validation. The peptides generated using GOOSE may not be suitable for in vivo use and may require additional testing to ensure their safety and efficacy. Researchers are advised to consult with a qualified expert and follow established guidelines for the handling and use of peptides in their laboratory.