Rational design of disordered proteins for sequence-function investigation
TL;DR
GOOSE is presented, a comprehensive computational framework for the rational design of IDRs that uses rational sequence design as a powerful method for exploring function in IDRs and provides a versatile tool for designing novel, functional disordered proteins.
Abstract
SUMMARY Despite lacking a stable three-dimensional structure, intrinsically disordered protein regions (IDRs) are ubiquitous across all kingdoms of life and play essential cellular roles1. While rational design of folded proteins has seen substantial recent progress2, our ability to design IDRs remains more limited3. Here, we present GOOSE, a comprehensive computational framework for the rational design of IDRs. GOOSE’s versatility and throughput enable us to design and test thousands of IDR sequences to reveal distinct sequence-to-function relationships. By using GOOSE to explore these relationships, we examine 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. Our work uses rational sequence design as a powerful method for exploring function in IDRs and provides a versatile tool for designing novel, functional disordered proteins.