Structural and Functional Relevance of Charge Based Transient Interactions inside Intrinsically Disordered Proteins

Area of Science:

• Biochemistry and Molecular Biology
• Protein Structure and Dynamics
• Biophysics

Background:

• Intrinsically disordered proteins (IDPs) lack stable structures, existing as flexible ensembles governed by weak interactions.
• Emerging evidence suggests transient, specific interactions influence IDP conformational behavior beyond homopolymer theory.
• Understanding the drivers of these specific interactions is crucial for elucidating IDP function.

Purpose of the Study:

• To investigate how the spatial arrangement of charged amino acids in IDP sequences influences transient, specific interactions.
• To establish a quantitative relationship between sequence properties and the prevalence of transient interactions.
• To explore the impact of these interactions on IDP behavior in phase-separated condensates and their functional relevance.

Main Methods:

• Utilized model peptides to establish an empirical relationship between transient interactions and effective charged patch length.
• Examined IDP ensembles with varying transient interaction levels in simulated phase-separated condensates.
• Performed a proteome-wide scan of disordered regions in the human proteome for charge-based transient interactions.

Main Results:

• Introduced 'effective charged patch length' as a metric quantifying the ability of charged patches to drive transient interactions.
• Observed the formation of a condensate-spanning network structure in IDP ensembles with significant transient interactions.
• Identified that approximately 10% of human disordered regions exhibit charge-driven transient interactions, leading to heteropolymeric behavior.

Conclusions:

• The spatial arrangement of charged residues significantly impacts transient interaction prevalence in IDPs.
• Charge-driven transient interactions promote heteropolymeric structural behavior in IDPs, particularly within phase-separated condensates.
• These interactions are enriched in specific molecular functions, highlighting their biological significance.