Frustration in Fuzzy Protein Complexes Leads to Interaction Versatility.

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Disordered proteins act as crucial interaction hubs, binding to multiple partners.
• While free disordered protein states are understood, mechanisms for multi-partner specificity remain unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying specificity in disordered protein interactions with multiple partners.
• To investigate the role of protein frustration in achieving specific binding modes.

Main Methods:

• Applied the energy landscape theory and the concept of protein frustration.
• Analyzed local frustration patterns at binding interfaces in protein complexes.

Main Results:

• Disordered protein complexes exhibit significant local frustration, particularly at binding interfaces.
• Suboptimal interactions lead to multiple, distinct bound substates with unique frustration patterns.
• These substates are differentially populated when binding to different partners.

Conclusions:

• Protein frustration explains how disordered proteins achieve specificity without a single bound conformation.
• The interplay of conflicting interactions allows disordered proteins to control binding to multiple partners.