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Nonequilibrium error-correction mechanisms, such as kinetic proofreading, enable biological systems to amplify the discrimination among cognate and non-cognate substrates beyond what is possible at equilibrium. However, it remains unclear how such discrimination should be distributed over the underlying network to achieve the full nonequilibrium advantage of error reduction. Using a discrete-state stochastic framework, we first show that the Hopfield network, the seminal model of proofreading, with discrimination concentrated in two dissociation steps, displays distinct regimes of error reduction depending on the relative magnitudes of the rate constants of various steps. One such regime is actually anti-proofreading, showing no improvement in accuracy with increasing discrimination. In contrast, a biologically realistic model of the tRNA selection network in protein translation by the E. coli ribosome exhibits distributed discrimination. We demonstrate that the spread of discrimination across the entire network enables the system to achieve the full nonequilibrium advantage, even in the kinetic regime where the Hopfield network lies in the anti-proofreading zone at low discrimination strength. Our results further indicate that excessively strong discrimination adversely affects the system, eliminating the nonequilibrium advantage of error reduction without providing any additional gain in the speed of translation.
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The energy cost and optimal design of networks for biological discrimination
Many biological processes discriminate between correct and incorrect substrates through the kinetic proofreading mechanism that enables lower error at the cost of higher energy dissipation. Elucidating physico-chemical constraints for global minimization of dissipation and error is important for understanding enzyme evolution. Here, we identify theoretically a fundamental error–cost bound that tightly constrains the performance of proofreading networks under any parameter variations preserving the rate discrimination between substrates. The bound is kinetically controlled, i.e. completely determined by the difference between the transition state energies on the underlying free energy landscape. The importance of the bound is analysed for three biological processes. DNA replication by T7 DNA polymerase is shown to be nearly optimized, i.e. its kinetic parameters place it in the immediate proximity of the error–cost bound. The isoleucyl-tRNA synthetase (IleRS) of E. coli also operates close to the bound, but further optimization is prevented by the need for reaction speed. In contrast, E. coli ribosome operates in a high-dissipation regime, potentially in order to speed up protein production. Together, these findings establish a fundamental error–dissipation relation in biological proofreading networks and provide a theoretical framework for studying error–dissipation trade-off in other systems with biological discrimination.
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- PAR ID:
- 10324759
- Date Published:
- Journal Name:
- Journal of The Royal Society Interface
- Volume:
- 19
- Issue:
- 188
- ISSN:
- 1742-5662
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.1098/rsif.2021.0883
