Thermodynamic constraints on kinetic proofreading in biosynthetic pathways.

We develop a quantitative theory of kinetic proofreading with an arbitrary number of checking steps after the hydrolysis of a nucleoside triphosphate. In particular, we investigate the relationship between the minimum dissipation of free energy required for a given error frequency in such systems. Several conclusions can be drawn from the present treatment: first, the ultimate accuracy of error correcting selective pathways is set by the displacement from equilibrium of the nucleoside triphosphates. Second, it is advantageous to achieve a desired accuracy at a small energy dissipation with several checking steps rather than a single one. This could explain antinomies in the amino acylation reaction as well as in mRNA translation, where small structural differences lead to large differences in flow rates between right and wrong substrates. Third, all checking steps should contribute equally to the accuracy, which implies a specific and symmetrical set of rate constants for the checking events on the enzyme.