Captivity selects for smaller eyes

combination of kinetic proofreading and induced fit in tRNA selection provides a suitable balance between fidelity and rapid elongation rates. If we take the simplest case of kinetic proofreading, where there are no differences in forward rate constants introduced by induced fit — where k 3 and k 5 are equivalent for both cognate and near-cognate tRNAs — significant discrimination between cognate and near-cognate tRNAs will only be observed when k 3 and k 5 are very, very slow relative to k –2 and k 7. In other words, if tRNA selection were an equilibrium process where the full discrimination potential was extracted from the binding energy, there would be no need for other discriminatory mechanisms. But such a slow step in translation is apparently not compatible with the overall rapid rate of elongation. The addition of induced fit to the process of tRNA selection boosts selectivity when the reaction is constrained to be fast by accelerating the rate of passage of cognate species relative to near-cognate ones. Because forward rates are fast relative to reverse ones, the selectivity of each step is lower than the theoretical maximum allowed by intrinsic energetic differences between cognate and near-cognate tRNAs in the complex. In this case, the energetic cost of inducing conformational changes has little impact on cognate tRNA selection but has substantial detrimental effects on near-cognate tRNA selection thus conferring increased specificity. Effects on forward rates that result from an induced fit mechanism have been shown to be a dominant determinant of fidelity in tRNA selection. A body of experimental data supports this idea by showing that miscoding increases when the differences in GTPase activation and accommodation rates are decreased either by introduction of a mutation in the tRNA body or by addition of antibiotics like paromomycin and streptomycin. We have discussed two general mechanisms used to maintain the high fidelity of protein synthesis (as well as of DNA replication and transcription). The first mechanism is comprised of editing and kinetic proofreading. Although different in detail, both strategies amplify the available discrimination power, determined by differences in free energy of binding, by having more than one selective step. Of these two strategies, editing has an advantage arising from the use of two distinct sites that scrutinize different properties of the substrate. The second mechanism, induced fit, depends on substrate-specific conformational changes that result in selective modulation of forward rate constants, permitting …