Intuitive, but not simple: including explicit water molecules in protein-protein docking simulations improves model...

Area of Science:

• Computational Biology
• Structural Biology
• Biophysics

Background:

• Protein-protein interactions are crucial for biological processes.
• Accurate prediction of protein complex structures is essential for understanding function.
• Existing computational docking methods often neglect the role of interfacial water molecules.

Purpose of the Study:

• To develop and evaluate a computational protein-protein docking strategy that explicitly includes bridging water molecules.
• To assess the impact of interfacial waters on the accuracy of predicting native-like protein complex structures.
• To improve the scoring and ranking of docked protein models.

Main Methods:

• Utilized the Hydropathic INTeractions (HINT) force field for scoring docked models.
• Applied the HINT water Relevance metric to identify bridging waters at protein-protein interfaces.
• Integrated identified bridging waters into the ZDOCK rigid body docking program for

Main Results:

• A statistically significant improvement of approximately 24% in the average hit-count within the top-10 predictions was observed compared to standard

Conclusions:

• Explicitly accounting for bridging water molecules in computational protein-protein docking enhances the accuracy of predicting native-like complex structures.
• Solvated docking improves the energetic contributions and physical representation of protein-protein interfaces.
• This approach offers a more realistic modeling of protein association by considering the role of water.