Theory formation in postulating enzyme kinetic mechanisms: reasoning with constraints

This paper reports on a prototype system for modeling and analyzing the expert reasoning involved in postulating enzyme kinetic mechanisms. It involves data-driven, theory-driven, and analogical components of reasoning within a generate-and-test cycle. Its central component is a set of domain-specific "filters" for matching experimentally and theoretically derived constraints. The input to the system consists of an abstracted qualitative description of an experiment and prior knowledge reported in the literature. Its output shows how the results match those expected for a set of postulated reaction mechanism models and also provides a trace of which features do or do not match each of the candidate topological models. Results, constraints, and models are all analyzed and compared to those from other, similar experiments. We deduced rules for interpreting the qualitative features of enzyme kinetic experiments from natural language descriptions in the literature and verified that the rules were correct by predicting the results for typical mechanisms. We obtained the correct behavior for all 37 states of a complex enzyme mechanism involving three substrates and three products. We tested our system on data from several published reports dealing with the enzyme hexokinase and obtained detailed listings of the differences in conclusions and interpretation reported in several journal articles. This system, which provides qualitative representations of enzyme kinetic results, should facilitate further experimentation on theory formation in enzyme kinetics and lead to more efficient experimental designs.