A25.00003. Trade-Offs and Kinetic Control for Kinetic Proofreading Networks in Biological Systems

Presented by: Joel D. Mallory


Abstract

Complex biological processes are known for their remarkable ability to select the correct substrate out of a pool of chemically similar substrates. Indeed, the enzymes that mediate the biological processes of DNA replication, mRNA transcription, and protein translation can activate so-called kinetic proofreading (KPR) mechanisms to enhance their accuracy at the cost of additional energy expenditure from futile cycles. What physicochemical properties of the participating enzymes are most important for the functionality of these biological processes with KPR? Upon investigating trade-offs between four physicochemical properties, namely, error rate, speed, noise, and energy dissipation, for the T7 DNA polymerase and Escherichia coli ribosome, we determined that these properties cannot all be optimized at the same time due to trade-offs between them. In addition, we ranked the importance of the properties and found that the enzyme speed is most important followed by the energy dissipation, error rate, and noise. Furthermore, another intriguing aspect of biological systems is their ability to regulate the stationary fluxes of the elementary biochemical reactions, but the fundamental factors that govern the flux regulation are not well understood. Which features of the underlying free energy landscape control the stationary flux distribution of biological systems? We have proven that the ratios of the steady-state fluxes are invariant to energy perturbations of the intermediate states and are only affected by the transition state energy barriers on the free energy landscape. Therefore, we have established that the physicochemical properties that depend on the steady-state flux ratios (e.g., the error rate and energy dissipation) are purely under kinetic and not thermodynamic control. The invariance proof has revealed important implications for various drug perturbations and genetic mutations to influence the physicochemical properties of a wide range of biological processes. For example, we illustrated the generality of the invariance proof for protein folding motivated by hen egg-white lysozyme, aminoacyl-tRNA selection during protein translation in the E. coli ribosome, and the myosin-V motor protein that walks on actin cytoskeleton filaments.

Authors

  • Joel D. Mallory
  • Anatoly B. Kolomeisky
  • and Oleg A. Igoshin


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