Energy considerations for kinetic proofreading in biosynthesis

Blomberg, Clas; Ehrenberg, M

doi:10.1016/0022-5193(81)90242-3

Cited by 20 publications

(13 citation statements)

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“…The above works identified the conditions necessary to minimize dissipation for a fixed error rate within the bounded regime. These works also identified kinetic limits in which such networks are fast and accurate over a finite interval of n. We elaborate further on the relationship between the time-error tradeoff found in our paper and that in (3)(4)(5)(6) in the SI Appendix.…”

Section: Resultsmentioning

confidence: 99%

Speed, dissipation, and error in kinetic proofreading

Murugan

Huse

Leibler

2012

Proc. Natl. Acad. Sci. U.S.A.

174

220

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Proofreading mechanisms increase specificity in biochemical reactions by allowing for the dissociation of intermediate complexes.These mechanisms disrupt and reset the reaction to undo errors at the cost of increased time of reaction and free energy expenditure. Here, we draw an analogy between proofreading and microtubule growth which share some of the features described above. Our analogy relates the statistics of growth and shrinkage of microtubules in physical space to the cycling of intermediate complexes in the space of chemical states in proofreading mechanisms. Using this analogy, we find a new kinetic regime of proofreading in which an exponential speed-up of the process can be achieved at the cost of a somewhat larger error rate. This regime is analogous to the transition region between two known growth regimes of microtubules (bounded and unbounded) and is sharply defined in the limit of large proofreading networks. We find that this advantageous regime of speed-error tradeoff might be present in proofreading schemes studied earlier in the charging of tRNA by tRNA synthetases, in RecA filament assembly on ssDNA, and in protein synthesis by ribosomes.enzyme-substrate reaction | nonequilibrium thermodynamics | speed-error trade-off | dynamic instability K inetic proofreading is a mechanism for error correction in biochemical processes, introduced in 1974 by John Hopfield (1) and independently by Jacques Ninio (2). Proofreading mechanisms enhance the effect of small differences in binding energy on reaction rates at the cost of consuming extra free energy. Such mechanisms involve a network of parallel pathways leading to product formation, in contrast to linear Michaelis-Menten-like schemes. When undesirable reactants participate in a reaction, free energy is used to drive the molecular system in cycles through these pathways, revisiting chemical intermediates many times before completing the reaction (1, 2).Such cycling is central to the error correcting properties of such schemes. On the other hand, the cycling has a cost in the form of increased time and energy to form products. While keeping error rates low is important in biological processes like protein synthesis, DNA replication and other enzyme-substrate reactions, slowing down these processes can directly impact fitness of organisms by slowing down their growth and reproduction. The resulting speed vs accuracy tradeoff is central to many biological and evolutionary questions.We explore an analogy between the nonequilibrium dynamics of proofreading schemes and the nonequilibrium growth of microtubules. Despite very different biological and chemical underpinnings of these two processes, there is much in common in the statistics of their fluctuations. Through this analogy, we discover that proofreading schemes naturally have two distinct kinetic regimes of operation. In the traditional regime, all reactants are cycled, minimizing errors at a large cost in time and energy. However, we identify another regime where undesirable reactants are caught u...

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Section: Resultsmentioning

confidence: 99%

Speed, dissipation, and error in kinetic proofreading

Murugan

Huse

Leibler

2012

Proc. Natl. Acad. Sci. U.S.A.

174

220

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“…In addition to the original Hopfield mechanism ( Fig. 1(a)), they include the "delayed" mechanism [10], the multistep mechanism [12,13,40], the T-cell receptor mechanism [14,18] and generalised proofreading mechanisms [15][16][17].…”

Section: Dissociation-based Mechanismsmentioning

confidence: 99%

“…1(a) of the main text), we described in the main text how the asymptotic error rate of ε ∼ x −2 could be achieved, by assuming that the labels are allowable functions of x such that: deg(l D ) = deg(l C ) = It is helpful to introduce the notation R ≈ Q, for functions R(x), Q(x) which may not be allowable, to signify that lim x→∞ R/Q = 1. We can use this to calculate the asymptotic behaviour of the terms P (i j) in the entropy production rate (equation (12) of the main text). For instance,…”

Section: Derivation Of Equation (20) Of the Main Textmentioning

confidence: 99%

“…In cellular information processing, a biochemical mechanism is coupled to an environment of signals and substrates and carries out tasks such as detection [1][2][3][4][5], amplification [6][7][8], discrimination [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24], adaptation [25], searching [26] and learning [27][28][29][30]. As Hopfield pointed out in his seminal work on discrimination [9], systems operating at thermodynamic equilibrium have limited information processing capability and energy must be expended to do better [8].…”

Section: Introductionmentioning

confidence: 99%

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Energy-speed-accuracy relation in complex networks for biological discrimination

2018

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Discriminating between correct and incorrect substrates is a core process in biology, but how is energy apportioned between the conflicting demands of accuracy (μ), speed (σ), and total entropy production rate (P)? Previous studies have focused on biochemical networks with simple structure or relied on simplifying kinetic assumptions. Here, we use the linear framework for timescale separation to analytically examine steady-state probabilities away from thermodynamic equilibrium for networks of arbitrary complexity. We also introduce a method of scaling parameters that is inspired by Hopfield's treatment of kinetic proofreading. Scaling allows asymptotic exploration of high-dimensional parameter spaces. We identify in this way a broad class of complex networks and scalings for which the quantity σln(μ)/P remains asymptotically finite whenever accuracy improves from equilibrium, so that μ_{eq}/μ→0. Scalings exist, however, even for Hopfield's original network, for which σln(μ)/P is asymptotically infinite, illustrating the parametric complexity. Outside the asymptotic regime, numerical calculations suggest that, under more restrictive parametric assumptions, networks satisfy the bound, σln(μ/μ_{eq})/P<1, and we discuss the biological implications for discrimination by ribosomes and DNA polymerase. The methods introduced here may be more broadly useful for analyzing complex networks that implement other forms of cellular information processing.

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“…By this way, slight differences of dissociation rates are amplified and more opportunities are given to inappropriate substrates to leave the enzyme before incorporation [2]. Authors then showed that increasing the number of proofreading steps with irreversible ligand exit, can strikingly decrease the error rate [3,4]. In these studies, the successive rounds of substrate checking are fundamentally driven and energy-consuming, in line with the expected thermodynamic cost of accuracy.…”

Section: Introductionmentioning

confidence: 99%

The accuracy of biochemical interactions is ensured by endothermic stepwise kinetics

Michel

Boutin

Ruelle

2016

Progress in Biophysics and Molecular Biology

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The discerning behavior of living systems relies on accurate interactions selected from the lot of molecular collisions occurring in the cell. To ensure the reliability of interactions, binding partners are classically envisioned as finely preadapted molecules, evolutionarily selected on the basis of their affinity in one-step associations. But the counterselection of inappropriate interactions can in fact be much more efficiently obtained through difficult multi-step adjustment, whose final high energy state is locked by a fluctuation ratchet. The progressive addition of molecular bonds during stereo-adjustment can be modeled as a predominantly backward random walk whose first arrival is frozen by a micro-irreversible transition. A new criterion of ligand specificity is presented, that is based on the ratio rejection/incorporation. In addition to its role in the selectivity of interactions, this generic recipe can underlie other important biological phenomena such as the regular synthesis at low level of supramolecular complexes, monostable kinetic bimodality, substrate concentration thresholds or the preparation of rapidly depolymerizable structureswith stored energy, like microtubules. Keywords: Fluctuation ratchet; self-assembly; substrate selection; binding specificity; induced fit. IntroductionMacromolecular crowding is the rule in most cellular compartments, but only certain interactions are appropriate, which imposes stringent partner selection. The preference for appropriate over inappropriate interactions, is classically assumed to rely on optimal conformational preadjustment between co-evolved complementary macromolecules. This type of binding is exothermic, that is to say thermodynamically driven by stabilization, which can be monitored in microcalorimetry by a dissipation of heat. But beside this standard mode of binding, authors understood that other mechanisms should exist to discriminate closely related, wrong and correct substrates. This discernment is necessary for example in the case of polymerases which should accommodate different substrate molecules at each polymerization step [1,2]. To ensure the counterselection of undesired substrates, the activity of theses polymerases should be low enough and the probability of substrate dissociation relatively high. By this way, slight differences of dissociation rates are amplified and more opportunities are given to inappropriate substrates to leave the enzyme before incorporation [2]. Authors then showed that increasing the number of proofreading steps with irreversible ligand exit, can strikingly decrease the error rate [3,4]. In these studies, the successive rounds of substrate checking are fundamentally driven and energy-consuming, in line with the expected thermodynamic cost of accuracy. This property is however not necessary if spontanous thermal fluctuations can be exploited. The classical one-step lock-andkey binding can be stabilized by induced fit, but the importance of conformational adjustment is variable. Contrary to initial bin...

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Energy considerations for kinetic proofreading in biosynthesis

Cited by 20 publications

References 25 publications

Speed, dissipation, and error in kinetic proofreading

Speed, dissipation, and error in kinetic proofreading

Energy-speed-accuracy relation in complex networks for biological discrimination

The accuracy of biochemical interactions is ensured by endothermic stepwise kinetics

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