Strategies
to Calculate Water Binding Free Energies in Protein–Ligand
Complexes
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Abstract
Water
molecules are commonplace in protein binding pockets, where they can
typically form a complex between the protein and a ligand or become
displaced upon ligand binding. As a result, it is often of great interest
to establish both the binding free energy and location of such molecules.
Several approaches to predicting the location and affinity of water
molecules to proteins have been proposed and utilized in the literature,
although it is often unclear which method should be used under what
circumstances. We report here a comparison between three such methodologies,
Just Add Water Molecules (JAWS), Grand Canonical Monte Carlo (GCMC),
and double-decoupling, in the hope of understanding the advantages
and limitations of each method when applied to enclosed binding sites.
As a result, we have adapted the JAWS scoring procedure, allowing
the binding free energies of strongly bound water molecules to be
calculated to a high degree of accuracy, requiring significantly less
computational effort than more rigorous approaches. The combination
of JAWS and GCMC offers a route to a rapid scheme capable of both
locating and scoring water molecules for rational drug design