- Hydration site prediction with and without the presence of
bound ligand—The ligand-free (apo) protein structure should
be used to predict hydration sites for the purpose of computing
protein desolvation free energy. WATsite also allows for hydra-
tion sites prediction at the protein and ligand binding interface.
Partial charge of ligand may significantly influence the outcome
of desolvation free energy. The user can predict partial charges
in the mol2 file for the ligand with other tools, such as RESP
[32] charge by using QM packages. Otherwise, the partial
charges are computed via AM1-BCC [33] method using
antechamber [22]. - Protein desolvation free energy—It is worth noting that the
estimated desolvation free energy for a ligand only represents
the energy of releasing the water molecules from the protein
binding site into the bulk solvent. It cannot be used for a direct
comparison of the ligands’ free energies of binding. The
ligand’s free energy of binding includes other important con-
tributions such as the direct protein–ligand interaction energy
or desolvation energy of the ligand. The predicted protein
desolvation free energy, however, can guide further optimiza-
tion of a lead compound rationally stabilizing or replacing
additional water molecules in the binding site.
Acknowledgment
We thank Andrew McNutt for testing the program and critical
reading. The authors gratefully acknowledge a grant from the
NIH (GM092855) for partially supporting this research.References
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