Kinetic Proofreading and the Limits of 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 ∼ 5 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.

Thermodynamic constraints on the assembly and diversity of microbial ecosystems are different near to and far from equilibrium

“…However, when these mechanisms have indeed been considered, they are implicitly assumed to be dissipating sufficient free-energy that thermodynamic constraints can reasonably be neglected. In contrast, in biophysics, non-equilibrium thermodynamics at the cellular level have been considered in much greater detail [ 7 ], particularly in the areas of kinetic proofreading [ 8 ] and sensing accuracy [ 9 , 10 ]. This opens the possibility of detailed consideration of the impact of thermodynamic constraints on ecosystem dynamics.…”

Slowest-first protein translation scheme: Structural asymmetry and co-translational folding

“…Production of functional proteins from mRNA comprises two concerted processes: directional translation and cooperative folding. The rate of translation is limited by trade-offs between speed, accuracy, and dissipation (11)(12)(13)(14). Folding quickly has certain advantages: unfolded proteins lead to aggregation, putting a significant burden on the cell (15)(16)(17); faster folding allows quicker responses to environmental changes (18,19).…”

Principles of Low Dissipation Computing from a Stochastic Circuit Model

“…30 These theoretical results have found application in many biological processes that natively operate near thermal energy scales. [31][32][33][34][35][36] Placed in the context of artificial computing, these relationships have shed light on fundamental constraints on the design of computing devices to minimize thermodynamic costs. 3,4,[37][38][39][40] While such theoretical results are general, to apply them to the problem of computing design requires a realistic physical representation of information processing, such as bit storage, measurement, and erasure.…”