Detailed discussion of the methodology and results around parameterization are provided in the Supporting Information. Some of the key significant details will be highlighted here specific to parameter optimization. Bonds and angle parameters were not parameterized as they showed overlap with quantum mechanics results (Figure ). Optimizing the water interactions around sorgoleone yielded an improved fit, with a RMSE that is only one quarter of the error from the initial values provided by CGenFF (Table ). The distribution of charges on dihydrosorgoleone was relatively complex, in comparison to sorgoleone. Quantum mechanics results suggested a relatively high interaction energy for one of hydroxyl and adjacent water molecules. To satisfy this energy, a compromise must be made in the water interaction with lone pair of hydroxy oxygen (Table ). Similar to this case, the lone pair on the adjacent ether oxygen interaction energy is excluded to better fit other interaction energies.