with RMSE, MAE, and R 2 values of 2.43 kcal/mol, 2.03 kcal/mol, and 0.59, respectively. The error and correlation metrics for the FM method were in general the best, while in few exceptions it was at least top 2. Behind the FM method was the SILCS/LGFE/TIP3P/GCMC-MD method with RMSE, MAE, and R 2 values of 3.06 kcal/mol, 2.59 kcal/mol, and 0.40 respectively. Both DDM/FEP/MBAR/FM/RW and SILCS/LGFE/TIP3P/GCMC-MD methods achieved the best error metrics, however, they did not have the best correlation, which will be discussed shortly. Ordered by the RMSE error metric, the next six methods had values ranging from 3.77 kcal/mol to 4.68 kcal/mol while the lowest two methods ranged from 5.72 to 6.64 kcal/mol (Table and Figure ). The results showcase the diverse and variable performance of methods for this challenge.