Control of translation initiation: a model-based analysis from limited experimental data

We have built a detailed kinetic model of translation initiation in yeast and have used a novel approach to determine the flux controlling steps based on limited experimental data. An efficient parameter estimation method was adapted in order to fit the most uncertain parameters (rate constants) to in vivo measurements in yeast. However, it was found that there were many other sets of plausible parameter values that also gave a good fit of the model to the data. We therefore used random sampling of this uncertain parameter space to generate a large number of diverse fitted parameter sets. A compact characterization of these parameter sets was provided by considering flux control. In particular, we suggest that the rate of translation initiation is most strongly influenced by one of two reactions: either the guanine nucleotide exchange reaction involving initiation factors eIF2 and eIF2B or the assembly of the multifactor complex from its constituent protein/tRNA containing complexes. It is hoped that the approach presented in this paper will add to our understanding of translation initiation pathway and can be used to identify key system-level properties of other biochemical processes.