The equilibrated structures were then used as the initial structure for the free energy calculations. The solvation-free energy was computed using the multi-state Bennett's acceptance ratio method (MBAR) . The solute-solvent intermolecular interactions were coupled/decoupled using 15 total stages, where an independent 22 ns NPT simulation was performed for each stage. In the first stage (m=0), the solute-solvent interactions are turned off, corresponding to the solute in a noninteracting ideal gas state. From stages m=1 to 10, the solute-solvent electrostatic interactions remained off, while the solute-solvent intermolecular Lennard-Jones interactions were gradually turned on using a "soft-core" potential .