It is worth noting that two sets of binding enthalpy predictions were submitted for CB8, but this was too few to allow statistical analysis. The methods were the ABFE/Parsley-GAFF-BCC/TIP3P/MD/NoBuffer1 and the more accurate (for predicting binding enthalpy) entropy-enthalpy based method EE-MCC/GAFF2-AM1-BCC/TIP3P/MD/. Although the EE-MCC/GAFF2-AM1BCC/TIP3P/MD method yielded poor binding free energy predictions, binding enthalpy predictions were within 2 kcal/mol for 4/7 systems. On the other hand, the ABFE/Parsley-GAFF-BCC/TIP3P/MD/NoBuffer1 predicts 1/7 systems within 2 kcal/mol. The correlation was modest with a few outliers for the entropy-enthalpy method, while there was a larger error and there appeared to be some system-Table . Error metrics for all (ranked and non-ranked) SAMPL8 methods for all host-guest systems. The root mean square error (RMSE), mean absolute error (MAE), signed mean error (ME), coefficient of correlation (R 2 ), slope (m), and Kendall's rank correlation coefficient (Tau) were computed via bootstrapping with replacement. Shown are results for individual host categories, with upper and lower bounds of 95% confidence intervals shown in brackets. Statistics do not include optional host-guest systems CB8-G8, CB8-G9, and TEMOA-G3. Each method has an assigned unique submission ID (sid). An asterisk next to the method's name denotes a ranked submission, and a double asterisk denotes a reference calculation. Overall the predictive accuracy of methods for the GDCC dataset was on the higher end. Several methods achieved RMSE and the top performing method for the GDCC dataset was DDM/AMOEBA/BAR, which had the best RMSE and MAE values of 0.88 and 396 0.72 kcal/mol, as well as values of 0.79 (Table and Figure ). The ATM/GAFF2-AM1BCC/TIP3P/HREM method came in second 397 overall for the GDCC dataset. Although we observe that computational predictive power is higher overall for the GDCC dataset, there are still methods which have very poor predictive power with RMSE and MAE values as high as 4.91 and 3.95 kcal/mol and coefficients of determination as low as 0.01 (Figure and Table ). 3.1.3 Binding free energy of some host-guest systems were more difficult to predict accurately Some host-guest complexes of the CB8 dataset proved to be more difficult to predict accurately compared to other such complexes in SAMPL8. This may not come as a surprise since CB8 guests were drug-like molecules with more rotational degrees of freedom compared to GDCC guests, thus more complex to model accurately. GDCC guests were more fragment-like and relatively rigid.