Kinetic Proofreading: A New Mechanism for Reducing Errors in Biosynthetic Processes Requiring High Specificity

Abstract

The specificity with which the genetic code is read in protein synthesis, and with which other highly specific biosynthetic reactions take place, can be increased above the level available fiom free energy differences in intermediates or kinetic barriers by a process defined here as kinetic proofreading. A simple kinetic pathway is described which results in this proofreading when the reaction is strongly but nonspecifically driven, e.g., by phosphate hydrolysis. Protein synthesis; amino acid recognition, and DNA replication, all exhibit the features of this model. In each case, known reactions which otherwise appear to be useless or deleterious complications are seen to be essential to the proofreading function.

Basic statistical recipes for the emergence of biochemical discernment

“…Since this ratio is insufficient to explain the observed biological specificity, Hopfield and Ninio proposed that the quality of the substrates is further discriminated through an additional mechanism based on the combination of two ingredients: (i) the previously postulated time scale separation between the processes of non-covalent interaction and of covalent ligation of the substrate, and (ii) an energy-driven one-way transition whose frequency is written below k* (for example through hydrolysis of GTP for translation or NTP for polynucleotide polymerisation). The stronger this k* transition is driven, the less probable is the direct ligand rebinding to yield ES* (Hopfield, 1974). Using these conditions, the sigmoidal behaviour of this substrate selection mechanism can be evidenced by the global reaction rate.…”

“…This problem becomes acute for polymerases such as DNA polymerases, RNA polymerases and ribosomes, which should respect the genetically-programmed sequence of residues encoding life informations and avoid the synthesis of harmful aberrant proteins. In the example of translation, John Hopfield (Hopfield, 1974) and Jacques Ninio (Ninio, 1975) were intrigued by the low error rate of the ribosome in vivo, which contrasts with the relatively low affinity of loaded tRNA for polysomes observed in vitro. These authors proposed a mechanism which strongly amplifies the capacity of discrimination between the twenty amino acids.…”

Elucidation of T cell signalling models

“…Kinetic proofreading was first introduced to describe the accuracy of DNA replication and protein synthesis [15]. McKeithan [16] applied kinetic proofreading to T cell signalling and it is now a widely accepted model to account for ligand discrimination [6].…”

The Case for Absolute Ligand Discrimination: Modeling Information Processing and Decision by Immune T Cells

“…The control of the quality of immune response by a single kinetic parameter τ is reminiscent of the famous Hopfield-Ninio kinetic-proofreading (KPR) paradigm, first proposed in the context of DNA replication and protein translation [31,52]. In the immune context, McKeithan pointed out that subsequent to TCR-pMHC interactions, the receptor does internally go through several rounds of phosphorylation.…”