As the compound S08 may be denoted as an outlier (see details below), the analyses are performed separately for the dataset with and without the compound. The overall mean unsigned error (MUE) is 1.21 kcal/mol for the entire dataset, and 0.68 kcal/mol when pairs involving S08 are excluded. The mean signed errors (MSEs) are 0.62 kcal/mol and -0.06 kcal/mol for the dataset with and without S08, respectively. Except the pairs with S08, only one compound pair, S22-S20, has a predicted ∆∆G value which differs from the experimental data by >2 kcal/mol. The main difference between the two compounds are the 3 rotatable bonds at R2 (Table ). The rotation of these rotatable bonds leads to large conformational flexibilities in S22, which may need longer simulation time to get reliable prediction.