PlaceWaters: Real-time, explicit interface water sampling during Rosetta ligand docking.

Area of Science:

• Computational chemistry
• Structural biology
• Drug discovery

Background:

• Water molecules at protein-small molecule interfaces, known as bridging waters, form hydrogen bonds that influence binding.
• Accurate prediction of these waters can improve ligand docking simulations, but is often computationally expensive.
• Current methods may rely on crystallographic data, limiting their applicability.

Purpose of the Study:

• To introduce a resource-efficient Rosetta-based protocol, PlaceWaters, for predicting explicit interface bridging waters during ligand docking.
• To develop a method that does not require knowledge of crystallographic water positions in homologous structures.

Main Methods:

• Developed a coarse-grained, structure-based protocol named PlaceWaters using the Rosetta software.
• Tested the PlaceWaters protocol on a diverse benchmark set of protein-small molecule interactions.
• Compared the performance of PlaceWaters against other Rosetta-based docking protocols.

Main Results:

• PlaceWaters accurately and quickly predicts the locations of bridging waters at the protein-small molecule interface.
• The protocol's performance was validated on a diverse benchmark set.
• Results indicate improved accuracy in predicting docked structures when using PlaceWaters.

Conclusions:

• PlaceWaters offers a computationally efficient and accurate method for incorporating explicit bridging waters into ligand docking.
• This approach enhances the ability to computationally screen drug candidates by improving docking prediction accuracy.
• The protocol's independence from crystallographic data makes it broadly applicable in drug discovery efforts.