Quantifying Allosteric Communication via Both Concerted Structural Changes and Conformational Disorder with CARDS

Area of Science:

• Biophysics
• Computational Biology
• Structural Biology

Background:

• Allosteric communication is vital for biological processes but its physical basis is unclear.
• Current computational methods often overlook the role of protein disorder in allostery.
• Experimental evidence suggests protein disorder significantly contributes to allosteric signaling.

Purpose of the Study:

• Introduce a novel computational framework, CARDS, to quantify protein allosteric communication.
• Integrate both structural and disorder dynamics for a comprehensive analysis of protein communication.
• Apply CARDS to understand allosteric regulation in the Catabolite Activator Protein (CAP).

Main Methods:

• Developed the Correlation of All Rotameric and Dynamical States (CARDS) framework.
• Quantified protein disorder by classifying dihedral time evolution into ordered and disordered regimes.
• Applied CARDS to analyze allosteric communication pathways in Catabolite Activator Protein (CAP).

Main Results:

• CARDS successfully identified allosteric communication between cAMP-Binding Domains (CBDs) in CAP.
• Disorder-mediated correlations were found to dominate allosteric coupling between CBDs.
• CARDS accurately captured the enhanced role of disorder in communication for a CAP variant (S62F).
• Identified communication hotspots within CAP without prior knowledge.

Conclusions:

• CARDS provides a powerful new method for quantifying protein allosteric communication.
• Protein disorder plays a critical role in mediating allosteric effects.
• CARDS can be utilized to predict and understand allosteric mechanisms in various proteins.