AlphaFlex: Ensembles of the human proteome representing disordered regions

Area of Science:

• Structural Biology
• Computational Biology
• Biophysics

Background:

• Intrinsically disordered protein regions (IDRs) comprise over a third of the human proteome and are crucial for biological regulation.
• IDRs lack stable structures but are vital for functions like post-translational modifications, scaffolding, and biomolecular condensate formation.
• Current structural models often fail to capture the dynamic nature and biological relevance of IDRs.

Purpose of the Study:

• To develop a computational workflow (AlphaFlex) for generating accurate, atomistic conformational ensembles of proteins containing IDRs.
• To provide biologically relevant structural models that enable deeper functional insights into IDPs.
• To create a comprehensive resource of full-length protein models for proteins with IDRs.

Main Methods:

• Utilized AlphaFold2 to identify and model confident folded domains within proteins.
• Employed IDPConformerGenerator or IDPForge to calculate fully atomistic conformer ensembles for the intrinsically disordered regions.
• Integrated folded domains and IDR ensembles to generate complete, dynamic protein models.

Main Results:

• Successfully generated conformational ensembles for human proteins with IDRs from the AlphaFold2 database using the AlphaFlex workflow.
• Deposited AlphaFlex models into the Protein Ensemble Database, mirrored in UniProt, creating a valuable resource.
• Demonstrated the utility of AlphaFlex ensembles for various protein types, including scaffold proteins, regulatory proteins, and those involved in condensate formation.

Conclusions:

• AlphaFlex provides a transformative approach to modeling full-length proteins with IDRs, offering more realistic and biologically relevant structural insights.
• This resource enhances our ability to study the function and regulation of intrinsically disordered proteins.
• The generated ensembles are crucial for understanding protein dynamics and interactions in various biological contexts.