The individual and combined benefits of different non-equilibrium 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 reactions in the overall mechanism. We develop here a model of substrates selection comprising energy consuming steps and 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. 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. We show that, in our framework, the fastest and most accurate selection strategy relies on a combination of both mechanisms. 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.