It can be seen that the direction of the error (sign of ∆G prot conf ) is system-dependent and fully consistent between EQ and NEQ methods. As explained in the Supporting Information, a negative value indicates that the dominant contributor to these systematic errors are the conformational differences between apo and holo states of the protein. On the other hand, a positive value suggests that the protein structures in apo and holo states are similar (or identical) but other factors mainly contribute to the systematic errors. 11 out of 14 systems studied here (exceptions are CDK2, TYK2 and JNK1) have negative