Mallory, J. D. | Search bioRxiv

bioRxiv2020

Trade-Offs between Speed, Accuracy, and Dissipation in tRNAIle Aminoacylation

Living systems maintain a high fidelity in information processing through kinetic proofreading, a mechanism to preferentially remove incorrect substrates at the cost of energy dissipation and slower speed. Proofreading mechanisms must balance their demand for higher speed, fewer errors, and lower dissipation, but it is unclear how rates of individual reaction steps are evolutionary tuned to balance these needs, especially when multiple proofreading mechanisms are present. Here, using a discrete-state stochastic model, we analyze the optimization strategies in Escherichia coli isoleucyl-tRNA synthetase. Surprisingly, this enzyme adopts an economic proofreading strategy and improves speed and dissipation as long as the error is tolerable. Through global parameter sampling, we reveal a fundamental dissipation-error relation that bounds the enzymes optimal performance and explains the importance of the post-transfer editing mechanism. The proximity of native system parameters to this bound demonstrates the importance of energy dissipation as an evolutionary force affecting fitness. Graphical TOC Entry O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/027615v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@f4f4e1org.highwire.dtl.DTLVardef@1f8e45forg.highwire.dtl.DTLVardef@1591e16org.highwire.dtl.DTLVardef@1c650b0_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2019

Kinetic control of stationary flux ratios for a wide range of biochemical processes

One of the most intriguing features of biological systems is their ability to regulate the steady-state fluxes of the underlying biochemical reactions, however the regulatory mechanisms and their physicochemical properties are not fully understood. Fundamentally, flux regulation can be explained with a chemical kinetic formalism describing the transitions between discrete states with the reaction rates defined by an underlying free-energy landscape. Which features of the energy landscape affect the flux distribution? Here we prove that the ratios of the steady-state fluxes of quasi-first-order biochemical processes are invariant to energy perturbations of the discrete states and are only affected by the energy barriers. In other words, the non-equilibrium flux distribution is under kinetic and not thermodynamic control. We illustrate the generality of this result for three biological processes. For the network describing protein folding along competing pathways, the probabilities of proceeding via these pathways are shown to be invariant to the stability of the intermediates or to the presence of additional misfolded states. For the network describing protein synthesis, the error rate and the energy expenditure per peptide bond is proven to be independent of the stability of the intermediate states. For molecular motors such as myosin-V, the ratio of forward to backward steps and the number of ATP molecules hydrolyzed per step is demonstrated to be invariant to energy perturbations of the intermediate states. These findings place important constraints on the ability of mutations and drug perturbations to affect the steady-state flux distribution for a wide class of biological processes.

biophysics↗