Thermodynamics of interfacial changes in a protein-protein complex

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biophysics

Background:

• Biomacromolecular complex stability and function depend on interface structural modifications.
• Previous studies lacked quantitative analysis of these interfacial changes.

Purpose of the Study:

• To thermodynamically characterize interfacial changes in the Nuclease A (NucA)-NuiA protein complex.
• To quantify conformational free energy and entropy costs associated with complex formation.

Main Methods:

• All-atom molecular dynamics simulations of the NucA-NuiA complex and free proteins.
• Calculation of conformational free energy and entropy from dihedral angle histograms.
• Analysis of tertiary structure changes in NuiA.

Main Results:

• Protein-protein binding is dominated by interfacial structural and thermodynamic changes.
• Ordered basic residues of NucA and acidic residues of NuiA form stable electrostatic interactions at the interface.
• Significant alterations in interfacial water molecule structure and dynamics were observed, contributing to entropy loss.

Conclusions:

• The NucA-NuiA complex formation is driven by highly ordered interfacial interactions and stabilized by electrostatics.
• Interfacial water plays a crucial role in the entropic cost of complexation.
• Quantitative thermodynamic data supports existing structural insights into enzyme-inhibitor interactions.