Trade-Offs between Speed, Accuracy, and Dissipation in tRNA^Ile Aminoacylation

Abstract

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 enzyme's 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 EntryM a x i m a l A c c u r a c y M a x i m a l S p e e d Min imal Diss ipati on tRNA Ile synthetase 2 . CC-BY-NC-ND 4.

The energy cost and optimal design of networks for biological discrimination

“…Moreover, the error-cost bound in more complex biological proofreading networks can be readily derived by identifying the equivalents of f 1 and f 2 /f p since they already capture all the relevant features of the energy landscape. Next, we apply this technique to three real proofreading systems with parameters provided in previous studies [8,9,22] and discuss biological implications.…”

“…Besides error and energy dissipation, the reaction speed constitutes another important property of the proofreading system, shown to be optimized in processes such as replication and translation [8][9][10][11]. The interplay among speed, accuracy and energy dissipation in systems involving kinetic proofreading (KPR) has been studied in different contexts [8,9,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26], providing insights to both general KPR networks and specific biological systems achieving discrimination through KPR.…”

“…However, different reaction steps may have different priorities in the optimization of characteristic properties. In the KPR network of tRNA Ile aminoacylation, for instance, the amino acid activation step optimizes speed, but the amino acid transfer step optimizes dissipation [22]. A more global approach that examines the effect of simultaneously varying multiple rate constants might be better suited to understand the evolutionary principle and consequence in the placement of the rate constants.…”

“…A more global approach that examines the effect of simultaneously varying multiple rate constants might be better suited to understand the evolutionary principle and consequence in the placement of the rate constants. This approach reveals a global errordissipation constraint that illustrates the importance of minimizing the energy cost in tRNA Ile aminoacylation [22] and coronavirus genome replication [27]. The error-dissipation constraint defines a manifold along which the decrease in error will lead to increase in energy cost and vice versa.…”

“…The error-dissipation bound in these systems reveals important physical and biological insights. To demonstrate this, we study three examples whose reaction networks were previously characterized: DNA replication by T7 DNA polymerase, aminoacyl-tRNA selection by E. coli ribosome [8], and aminoacylation by E. coli isoleucyl-tRNA synthetase (IleRS) [22]. The global parameter sampling confirms that the error-dissipation bound is valid in these systems and that the non-equilibrium driving provided by hydrolyzing energy-rich molecules in the futile cycles is indeed sufficiently large, allowing for the bound to be closely approached.…”