The predictability of catalytic and binding sites from apo structures is addressed for proteins that undergo significant conformational change upon binding. Theoretical microscopic titration curves (THEMATICS), an electrostatics-based method for the prediction of functional sites, is performed on a test set of 24 proteins with both apo and holo structures available. For 23 of these 24 proteins (96%), THEMATICS predicts the correct catalytic or binding site for both the apo and holo forms. For only one of the 24 proteins, THEMATICS makes the correct prediction for the holo structure but fails for the apo structure. The metrics used by THEMATICS to identify functional residues generally are larger in absolute value for the functional residues in the holo forms compared to the corresponding residues in the apo forms. However, even in the apo forms, these identifying metrics are still statistically significantly larger for functional residues than for residues not involved in catalysis or binding. This indicates that some of the unusual electrostatic properties of functional residues are preserved in the apo conformation. Evidence is presented that certain residues immediately surrounding the active catalytic and binding residues impart functionally important chemical and electrostatic properties to the active residues. At least parts of these microenvironments exist in the unbound conformations, such that THEMATICS is able to distinguish the functional residues even in the apo structures.