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The Escherichia coli chemotaxis signaling pathway has served as a modelsystem for studying the adaptive sensing of environmental signals by largeprotein complexes. The chemoreceptors control the kinase activity of CheA inresponse to the extracellular ligand concentration and adapt across a wideconcentration range by undergoing methylation and demethylation. Methylationshifts the kinase response curve by orders of magnitude in ligand concentrationwhile incurring a much smaller change in the ligand binding curve. Here, weshow that this asymmetric shift in binding and kinase response is inconsistentwith equilibrium allosteric models regardless of parameter choices. To resolvethis inconsistency, we present a nonequilibrium allosteric model thatexplicitly includes the dissipative reaction cycles driven by ATP hydrolysis.The model successfully explains all existing measurements for both aspartateand serine receptors. Our results suggest that while ligand binding controlsthe equilibrium balance between the ON and OFF states of the kinase, receptormethylation modulates the kinetic properties (e.g., the phosphorylation rate)of the ON state. Furthermore, sufficient energy dissipation is necessary formaintaining and enhancing the sensitivity range and amplitude of the kinaseresponse. We demonstrate that the nonequilibrium allosteric model is broadlyapplicable to other sensor-kinase systems by successfully fitting previouslyunexplained data from the DosP bacterial oxygen-sensing system. Overall, thiswork provides a new perspective on cooperative sensing by large proteincomplexes and opens up new research directions for understanding theirmicroscopic mechanisms through simultaneous measurements and modeling of ligandbinding and downstream responses.

Resolving the binding-kinase discrepancy in bacterial chemotaxis: A nonequilibrium allosteric model and the role of energy dissipation