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Dynamic cooperativity in monomeric enzymes is characterized in terms of anon-Michaelis-Menten kinetic behaviour. The latter is believed to be associatedwith mechanisms that include multiple reaction pathways due to enzymaticconformational fluctuations. Recent advances in single-molecule fluorescencespectroscopy have provided new fundamental insights on the possible mechanismsunderlying reactions catalyzed by fluctuating enzymes. Here, we present abottom-up approach to understand enzyme turnover kinetics at physiologicallyrelevant mesoscopic concentrations informed by mechanisms extracted fromsingle-molecule stochastic trajectories. The stochastic approach, presentedhere, shows the emergence of dynamic cooperativity in terms of a slowing downof the Michaelis-Menten (MM) kinetics resulting in negative cooperativity. Forfewer enzymes, dynamic cooperativity emerges due to the combined effects ofenzymatic conformational fluctuations and molecular discreteness. The increasein the number of enzymes, however, suppresses the effect of enzymaticconformational fluctuations such that dynamic cooperativity emerges solely dueto the discrete changes in the number of reacting species. These resultsconfirm that the turnover kinetics of fluctuating enzyme based on theparallel-pathway MM mechanism switches over to the single-pathway MM mechanismwith the increase in the number of enzymes. For large enzyme numbers,convergence to the exact MM equation occurs in the limit of very high substrateconcentration as the stochastic kinetics approaches the deterministicbehaviour.

Emergence of Dynamic Cooperativity in the Stochastic Kinetics of Fluctuating Enzymes