Structure and dynamics conspire in the evolution of affinity between intrinsically disordered proteins

Area of Science:

• Molecular Evolution
• Biophysics
• Structural Biology

Background:

• Protein-protein interactions are crucial for cellular function and evolve to be fit for purpose.
• The molecular mechanisms underlying the evolution of new protein-protein interactions remain poorly understood.

Purpose of the Study:

• To investigate structural and dynamic changes during the evolution of the CID/NCBD protein-protein interaction.
• To understand how these changes influence binding affinity over evolutionary timescales.

Main Methods:

• Nuclear magnetic resonance (NMR) spectroscopy was used to study the structure and dynamics of CID/NCBD complexes.
• Isothermal titration calorimetry (ITC) was employed to assess binding thermodynamics.

Main Results:

• The ancient "Cambrian-like" CID/NCBD complex (540-600 Ma) exhibited less secondary structure and higher dynamics compared to Ordovician-Silurian (440 Ma) and extant human complexes.
• The ancient complex had a larger solvent-accessible surface area and lacked key structural features.
• Binding affinity was enthalpically favorable but entropically unfavorable, with dynamics reducing over evolutionary time.

Conclusions:

• Changes in structure and dynamics are key drivers in shaping protein-protein complex affinity during evolution.
• Structural, dynamic, and "frustrational" plasticity play significant roles in the evolution of interactions involving intrinsically disordered proteins.