Rational design of disordered proteins for sequence-function investigation

Area of Science:

• Biochemistry
• Computational Biology
• Protein Engineering

Background:

• Intrinsically disordered protein regions (IDRs) lack stable 3D structures but are vital for cellular functions.
• Rational design of folded proteins has advanced, but designing IDRs remains challenging.

Purpose of the Study:

• To present GOOSE, a computational framework for the rational design of intrinsically disordered protein regions (IDRs).
• To explore sequence-to-function relationships in IDRs and enable the design of novel functional disordered proteins.

Main Methods:

• Development of the GOOSE computational framework (Generate disOrdered prOteins Specifying propErties).
• High-throughput design and testing of thousands of IDR sequences.
• Investigation of sequence properties influencing IDR structural ensembles in cellular environments.

Main Results:

• GOOSE facilitates the discovery of distinct sequence-to-function relationships in IDRs.
• Designed IDRs demonstrate responsiveness to cellular structural changes (e.g., volume decrease).
• Created scaffold IDRs capable of self-assembly and specific client recruitment.
• Engineered novel IDRs conferring desiccation protection to cells.

Conclusions:

• Rational sequence design is a powerful approach for understanding IDR function.
• GOOSE provides a versatile tool for designing functional disordered proteins with tailored properties.
• This framework opens new avenues for protein engineering and synthetic biology applications.