The KPC-2 carbapenemase enzyme is responsible for drug resistance in the majority of carbapenem-resistant Gram-negative bacterial infections in the United States. A better understanding of what permits KPC-2 to hydrolyze carbapenem antibiotics and how this might be inhibited is thus of fundamental interest and great practical importance to development of better anti-infectives. By correlating molecular dynamics simulations with experimental enzyme kinetics, we identified conformational changes that control KPC-2’s ability to hydrolyze carbapenem antibiotics. Related beta-lactamase enzymes can interconvert between catalytically permissive and catalytically nonpermissive forms of an acylenzyme intermediate critical to drug hydrolysis. Using molecular dynamics simulations, we identify a similar equilibrium in KPC-2 and analyze the determinants of this conformational change. Because the conformational dynamics of KPC-2 are complex and sensitive to allosteric changes, we develop an information-theoretic approach to identify key determinants of this change. We measure unbiased estimators of the reaction coordinate between catalytically permissive and nonpermissive states, perform information-theoretic feature selection, and, using restrained molecular dynamics simulations, validate the protein conformational changes predicted to control catalytically permissive geometry. We identify two binding-pocket residues that control the conformational transitions between catalytically active and inactive forms of KPC-2. Mutations to one of these residues, Trp105, lower the stability of the catalytically permissive state in simulations and have reduced experimental kcat values that show a strong linear correlation with the simulated catalytically permissive state lifetimes. This understanding can be leveraged to predict the drug resistance of further KPC-2 mutants and help design inhibitors to combat extreme drug resistance.