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How should I treat water molecules in the active site while preparing my target structure, and how does Glide treat water molecules that are in the active site?

Water molecules that mediate receptor-ligand interactions (so-called "structural waters" that bridge the receptor and ligand by way of H-bonds) can be retained during target preparation. In the Glide docking experiment, these waters will be retained and treated as part of the receptor environment — for example, a ligand H-bond to a water molecule will receive an energetic reward, the exact value of which depends on interaction geometry and the surrounding environment (not unlike a ligand H-bond to a protein residue).

During target preparation, you will need to make an informed decision about which water molecules to retain in the active site and which water molecules should be deleted before the docking experiment is carried out. Among other things, deleting unnecessary water molecules allows the active site to accommodate novel ligands that wouldn't otherwise fit.

One way of making these informed decisions is by consulting publications that describe the active site. There are also computational tools that can help in deciding which water molecules to retain. One such computational method is to align different PDB structures of the same target, color the structures by entry number in the Workspace, and look for highly conserved water molecules. The idea here is that highly conserved water molecules are important for binding.

It is known that in some targets, a structural water can be replaced by a ligand with a functional group that forms the same H-bonds to the receptor that the water molecule did. If you suspect this may be the case for the prepared target, you may choose to retain or displace the water molecule depending on the chemotype of the ligands being docked. Such instances can be treated by preparing two versions of the target - one that retains the water and one that removes it. A single ligand library can then be docked against both target models in a single experiment using our Virtual Screening Workflow interface, which automatically sorts and filters the results.

Note that the Glide SP and XP scoring functions both include terms that are designed to account for solvation of the active site. Thus, water molecules do not need to be added to the active site in order to obtain an estimate of desolvation effects. For example, the energetics of desolvation account for the extra reward term that is incurred by hydrophobic ligand groups that are fully enclosed by hydrophobic receptor residues. Glide XP further accounts for the energetics of desolvation by placing so-called "virtual waters" in the active site to estimate water displacement and ligand-solvent interactions.

Keywords: Glide, docking, water, structural waters, solvent, solvation

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