Individual and combined benefits of different nonequilibrium proofreading mechanisms

Genome duplication, transcription, and translation are among many crucial cellular processes that need to be performed with high fidelity. However, those extremely low error rates cannot be explained with simple equilibrium thermodynamic considerations. They instead require considering irreversible, energy-consuming re-actions in the overall mechanism. We develop here a model of substrates selection comprising energy-consuming steps which aims at selecting right substrates among wrong ones. With this model, we investigate the impact of energy consumption on the accuracy and the speed of the selection, as well as different selection strategies, by unraveling the molecular steps underlying the discrimination process. The model presented here encompasses the classic kinetic proofreading scheme and a different mechanism whereby the rates of the energy-consuming step are modulated by the nature of the substrate, the catalytic discrimination. We show that, in our framework, the fastest and most accurate selection strategy relies on a combination of both mechanisms, a reliable strategy to overcome the speed-accuracy tradeoff. A structurally and biochemically informed coarse-grained description of real biological processes such as DNA replication and protein translation, traditionally used as examples of kinetic proofreading at work, shows that, as a matter of fact, a combination of both mechanisms explored here is exploited.