EC scores would lose linear correlation if such a water molecule is removed in this case, indicating the strength of hydrogen bonding formed in this way can influence the activity. Another case also shows the difficulty to have linear correlation between EC scores and activity when the position of bridge water is not well determined (vide infra). EC score is not a universal predictor. There is no linear relationship between EC score and bioactivity in many cases we have studied. Therefore, we defined the EC application boundaries for EC scores' application. We summarized specific areas where the EC score fails to give a linear relationship to activity as following: