Improving protein-ligand docking with flexible interfacial water molecules using SWRosettaLigand

Area of Science:

• Computational chemistry
• Structural biology
• Drug discovery

Background:

• Protein-ligand docking is crucial for drug discovery and design.
• Conformational changes, particularly involving water molecules and receptor interfaces, significantly impact docking accuracy.
• Existing protocols may not adequately account for these dynamic aspects.

Purpose of the Study:

• To develop an improved computational protocol for protein-ligand docking.
• To enhance accuracy by incorporating flexibility of interfacial water molecules and receptor backbone interfaces.
• To refine the RosettaLigand protocol for better performance in drug design.

Main Methods:

• Developed SWRosettaLigand, an enhanced version of the RosettaLigand protocol.
• Incorporated pre-optimization of interfacial water molecules and modeling of receptor interface flexibility.
• Employed kinematic closure or cyclic coordinate descent for refining receptor backbone dynamics during docking.

Main Results:

• SWRosettaLigand demonstrated improved accuracy in cross-docking tests.
• Achieved better top-ranked structure accuracy in 8 out of 14 and 16 out of 22 test instances compared to other protocols.
• Successfully integrated explicit water molecules and receptor interface flexibility into the docking process.

Conclusions:

• The SWRosettaLigand protocol offers enhanced accuracy for protein-ligand docking.
• Modeling interfacial water and receptor flexibility is critical for improving docking predictions.
• This method holds promise for advancing computational drug discovery and design.