Specificity, sensitivity, and energy dissipation in kinetic proofreading: a mechanistic revisit

Cellular signaling, crucial for processes like immune response and homeostasis, requires specificity and fidelity for accurate responses to stimuli amidst environmental noise. Kinetic proofreading (KPR) enhances signaling specificity. Kinetic proofreading (KPR) enhances signaling specificity by utilizing multiple intermediate energy-consuming steps during receptor activation. However, how much of this KPR-mediated enhancement is eroded by noise is debated, particularly in cases that involve many intermediate steps.

To understand the impact of the number of KPR activation steps on specificity, sensitivity, energy consumption, and accuracy, we develop a simplifying model that captures the essential dynamics by condensing multiple steps into a single one with a non-Markovian waiting time. We find analytic expressions for system specificity and sensitivity, that depends on how the signal output is interpreted. Specifically, in T cell signaling, we identify a variant of KPR that improves recognition accuracy and speed.

To assess the energy efficiency of KPR, we explore different networks of KPR steps with varied kinetic parameters. We find that incremental resetting of receptor activation states, compared to the commonly assumed full receptor resetting approximation, enhances energy efficiency without compromising accuracy. These findings provide insights into KPR design principles and their potential biological realizations.