Electrostatic contributions to protein-protein binding affinities: application to Rap/Raf interaction

Area of Science:

• Computational chemistry
• Biophysics
• Molecular modeling

Background:

• Accurate calculation of protein-protein binding free energies is essential for understanding biological processes.
• Existing models often struggle with the complexities of protein reorganization upon complex formation.

Purpose of the Study:

• To evaluate the scaled Protein Dipoles Langevin Dipoles (PDLD/S) model combined with the Linear Response Approximation (LRA) for calculating absolute binding free energies of protein-protein complexes.
• To investigate the impact of protein reorganization on binding energy calculations.
• To assess the contributions of individual residues to binding free energy.

Main Methods:

• Utilized the scaled Protein Dipoles Langevin Dipoles (PDLD/S) model with the Linear Response Approximation (LRA).
• Employed the Rap1A-Raf-RBD complex as a model system.
• Explored various formulations and thermodynamic cycles, considering protein relaxation explicitly and implicitly.

Main Results:

• Explicit consideration of protein relaxation is critical for accurate binding free energy calculations, especially with low implicit dielectric constants.
• A simplified non-relaxed approach can qualitatively assess group contributions to binding energy.
• More residues than typically assumed, including those not at the interface, significantly contribute to the Raf-RBD/Rap binding energy through charge-charge interactions.

Conclusions:

• Protein relaxation is a key factor in accurate binding free energy predictions.
• While challenging, implicit treatment of protein reorganization can capture qualitative trends of mutations.
• The PDLD/S model with LRA provides a valuable framework for analyzing protein-protein interactions, highlighting the importance of non-interface residues.