The GIST method estimates the thermodynamics properties of water in the context of a protein receptor . Thermodynamics properties are derived from MD trajectories by discretizing a defined region of interest, such as a ligand binding site, into voxels in a 3D grid with a resolution of 0.5 Å 2 . Similarly, ensembles generated with WaterKit were processed as MD trajectories using the standard GIST protocol. Different types of grids are calculated to describe solvent-related thermodynamic properties of the system (all expressed in kcal/mol/Å 3 ): solute-water enthalpy (E sw ), water-water enthalpy (E ww ), translational entropy (TS trans ) and orientational entropy (TS orient ). Water oxygen and hydrogen densities (gO and gH, respectively) can also be calculated and expressed as the ratio between the measured grid density over the bulk density (i.e.: density/bulk density units). Therefore, voxels with a value of 1, means that the density is equal to the bulk density. In this study, the desolvation free energy ∆G solv grid was obtained using the following equation :