THEMATICS: A simple computational predictor of enzyme function from structure

We show that theoretical microscopic titration curves (THEMATICS) can be us ed to identify active-site residues in proteins of known structure. Results are featured for three enzymes: triosephosphate isomerase (TIM), aldose re ductase (AR), and phosphomannose isomerase (PMI). We note that TIM and AR h ave similar structures but catalyze different kinds of reactions, whereas T IM and PMI have different structures but catalyze similar reactions. Analys is of the theoretical microscopic titration curves for all of the ionizable residues of these proteins shows that a small fraction (3-7%) of the curve s possess a flat region where the residue is partially protonated over a wi de pH range. The preponderance of residues with such perturbed curves occur in the active site. Additional results are given in summary form to show t he success of the method for proteins with a variety of different chemistri es and structures.