|Enzymes are essential protein catalysts that regulate most important biological processes. Enzymes act by converting starting molecules into different molecules. Our ability to control the function of enzymes via rational design will significantly improve our understanding of protein structure-function relationships and transform our ability to control biological processes (e.g., creating temperature adaptive proteins for biomedical and bioindustrial applications). Our current inability to predict the role of the protein scaffold structure and corresponding feedback mechanisms upon mutation reflects a significant gap in our understanding of enzyme function beyond the catalytic-site structure and to design enzymes that function outside of standard physiological conditions. Our current effort has focused on developing a novel computational protein design strategy to rationally design temperature-adapted enzymes. This project is innovative, because it represents a new and substantive departure from fixed-backbone enzyme design. Namely, we developed a discrete multistate enzyme design cycle (i.e., iterative hypothesis-driven multi-state enzyme modeling and experimental validation) that accurately captures structural and thermodynamic scaffold feedback properties to explicitly design conditional (temperature-adapted) enzymatic catalysis. Furthermore, we gained significant new insights into thermodynamic properties of enzyme structure function relationships.