With the leisure of time, kinetic proofreading can still perform reliable ligand discrimination

In a recent PNAS publication, Kirby and Zilman studied kinetic proofreading for receptor signaling and argued that having more proofreading steps does not generally improve ligand discrimination when stochastic effects are taken into account. In their analysis, however, the authors made an implicit assumption about a fixed discrimination time, which is not always warranted. We show that when the discrimination time is allowed to vary in order to maintain a fixed level of signaling activity, the proofreading performance can, in fact, uniformly improve with the number of steps. We therefore call for a comprehensive study of the interplay between discrimination time, discrimination accuracy, and signaling activity, where the two seemingly contradictory results will be slices of the trade-off surface along different axes.