Kinetic Proofreading and the Limits of Thermodynamic Uncertainty

TL;DR

This paper investigates how kinetic proofreading circuits like DNA polymerase and ribosomes operate near thermodynamic bounds, revealing that proximity to these limits enhances accuracy, efficiency, and overall performance.

Contribution

It demonstrates that DNA polymerase operates close to the thermodynamic uncertainty relation bound, while ribosomes are farther, highlighting differences in their kinetic discrimination and efficiency.

Findings

DNA polymerase operates near the TUR lower bound

Ribosome operates ~5 times farther from the TUR bound

Operating near the bound improves accuracy and reduces thermodynamic uncertainty

Abstract

To mitigate errors induced by the cell's heterogeneous noisy environment, its main information channels and production networks utilize the kinetic proofreading (KPR) mechanism. Here, we examine two extensively-studied KPR circuits, DNA replication by the T7 DNA polymerase and translation by the E. coli ribosome. Using experimental data, we analyze the performance of these two vital systems in light of the fundamental bounds set by the recently-discovered thermodynamic uncertainty relation (TUR), which places an inherent trade-off between the precision of a desirable output and the amount of energy dissipation required. We show that the DNA polymerase operates close to the TUR lower bound, while the ribosome operates $\sim5$ times farther from this bound. This difference originates from the enhanced binding discrimination of the polymerase which allows it to operate effectively as a reduced reaction cycle prioritizing correct product formation. We show that approaching this limit also decouples the thermodynamic uncertainty factor from speed and error, thereby relaxing the accuracy-speed trade-off of the system. Altogether, our results show that operating near this reduced cycle limit not only minimizes thermodynamic uncertainty, but also results in global performance enhancement of KPR circuits.