Effector-Binding-Directed Dimerization and Dynamic Communication between Allosteric Sites of Ribonucleotide Reductase

Area of Science:

• Biochemistry and Molecular Biology
• Computational Biophysics
• Enzymology

Background:

• Protein complex formation and function are often modulated by effector molecules binding to allosteric sites.
• Understanding the dynamic coupling between effector binding and protein interface formation is crucial for deciphering regulatory mechanisms.

Purpose of the Study:

• To investigate and quantify the coupling between effector binding and protein interface formation using computational simulations.
• To apply the developed method to ribonucleotide reductase (RNR), an essential enzyme in DNA synthesis.
• To elucidate the regulatory mechanisms of RNR's s-site and a-site.

Main Methods:

• Utilized computer simulations, including atomistic and coarse-grained molecular dynamics.
• Connected monomeric protein dynamics with oligomeric interface information to quantify contact interactions.
• Analyzed effector-protein dynamics and dimer interface formation at RNR's s-site and a-site.

Main Results:

• Demonstrated a positive coupling between effector-protein dynamics at the s-site and dimer interface formation in RNR.
• Quantified the resonance level between effector binding and interface formation at the s-site, applicable to other systems.
• Showed that different effectors (ATP vs. dATP) at the a-site significantly alter protein dynamics and enzyme activity.

Conclusions:

• The study provides a quantitative framework for understanding effector-mediated regulation of protein complex assembly.
• Proposed a novel mechanism for how the a-site of RNR regulates enzyme activity based on differential effector binding.
• Highlights the importance of dynamic coupling in allosteric regulation of essential enzymes like RNR.