Leveraging a Separation of States Method for Relative Binding Free Energy Calculations in Systems with Trapped Waters

Area of Science:

• Computational chemistry
• Structural biology
• Drug discovery

Background:

• Relative binding free energy (RBFE) calculations are vital in structure-based drug discovery.
• Handling interfacial waters in protein-ligand binding poses significant challenges for RBFE accuracy.
• Existing methods using enhanced sampling for trapped waters can lead to simulation hysteresis.

Purpose of the Study:

• To introduce and validate a novel "separation of states" method for RBFE calculations.
• To address inaccuracies in RBFE estimates caused by differing trapped water configurations between ligands.
• To provide a robust computational approach for ligand binding affinity prediction.

Main Methods:

• Developed a "separation of states" approach to decouple trapped water sampling from ligand transformation.
• Decoupled interfacial water, stabilized the resulting cavity, and grew a displacing ligand.
• Applied the method to five ligand pairs involving trapped water rearrangement.
• Optimized simulation protocols for large-scale distributed computing and automated the workflow.

Main Results:

• The "separation of states" method yields precise and accurate RBFE estimates.
• Successfully calculated RBFEs for ligand pairs with varying trapped water arrangements.
• Demonstrated the method's effectiveness in overcoming challenges posed by interfacial water dynamics.

Conclusions:

• The "separation of states" method offers a reliable alternative for RBFE calculations involving trapped waters.
• This approach enhances the accuracy and applicability of computational methods in drug discovery.
• The optimized and automated workflow facilitates broader use in research settings.