Enzymes catalyze chemical reactions many orders of magnitude faster than the uncatalyzed reaction and are capable of doing so at physiological pH and temperature. Consisting of hundreds of amino acids, the ability to identify which residues contribute to catalysis with high recall and low false positive rates becomes invaluable to characterizing and engineering enzymes. THEMATICS (Theoretical Microscopic Titration Curves) and POOL (Partial Order Optimum Likelihood) are programs designed at Northeastern University that can identify the residues contributing to catalysis. THEMATICS finds anomalous titration behavior, which correlates with catalytic activity. POOL combines the THEMATICS input with geometric and evolutionary predictions to rank each residue by the likelihood of its importance for catalysis. Alkaline phosphatase is a protein found in all domains of life which cleaves phosphate groups from a broad range of substrates. THEMATICS and POOL predicts that alkaline phosphatase contains most of its catalytic power in the residues directly surrounding the reacting substrate molecule; there is very little contribution from the residues in the second or third shells of the enzyme. This example is in stark contrast to PGI (human phosphoglucose isomerase) and nitrile hydratase (NH), where THEMATICS and POOL predict a multi-layer active site, with residues in the second and third shells contributing to activity (Brodkin et al. 2011 Biochemistry v 50 p 4923; Somarowthu et al. 2011 Biochemistry v 50 p 9283). These predictions for PGI and NH have been experimentally validated, bringing us closer to understanding the different ways that enzymes achieve such striking catalytic power.