where ∆G MM ele , ∆G MM vdW and ∆G MM int the electrostatic, van der Waals and the internal bonded contributions to the molecular mechanics free energy difference, respectively, and ∆G sol pol and ∆G sol nonpol are the polar and non-polar solvation terms, respectively. The MMPBSA.py program, provided as part of the AmberTools 14 package , was used in the evaluation of all components of the MMPBSA calculation. The electrostatic free energy of solvation, ∆G sol pol , is the part of the calculation described by the Poisson-Boltzmann (PB) calculation. Default values were used for the PB calculation (grid spacing of 0.5 Å, internal and external dielectric constants of 1 and 80, respectively). The non-polar solvation free energy calculation is calculated from the solvent accessible surface area using the traditional one component method (specified using inp=1 in the input file). In this approach the surface tension, γ, is set to 0.00542 kcal mol -1 Å -2 ) and the off-set β , to 0.92 kcal mol -1 . The fill ratio parameter was set to 4.0 which does not impact the results but ensures the stability of the calculations. For calculations in which explicit water molecules were incorporated as part of the receptor, the closest N molecules to the ligand were chosen for inclusion.