Large Scale Complex Protein Synthesis Networks: Modeling and Analysis of Translation Elongation Behavior

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The genetic information in DNA is transcribed to mRNA and then translated to proteins, which form the building blocks of life. Translation, or protein synthesis, is hence a central cellular process. Decades of experimentation have elucidated a vast wealth of molecular information about discrete translation steps, but the sheer complexity of the translation mechanism necessitates that these results be integrated in systematic mathematical frameworks to better understand the system properties of translation and make quantitative predictions. In this work we have developed a deterministic, sequence specific kinetic model of the translation mechanism that accounts for all its elementary steps. Specifically, our model includes all the elementary steps involved in the elongation cycle at every codon along the length of the mRNA. We performed a sensitivity analysis in order to determine the effects of the kinetic parameters and concentrations of the translational components on the protein synthesis rate. Utilizing our mechanistic framework and sensitivity analysis, we investigate the steady state protein synthesis properties of mRNAs. In this thesis we first introduce the mechanistic framework and sensitivity analysis, and we utilize them to investigate the protein synthesis properties of a single mRNA species. We then expand our mechanistic framework and sensitivity analysis to account for ternary complex competitive binding to the ribosomal A site to study effects of codon specific elongation cycle properties on the protein synthesis properties of mRNAs. We finally apply our expanded mechanistic framework and sensitivity analysis to all the genes in the E. coli genome. We determine (i) the interplay between ribosomal occupancy of elongation cycle intermediate states and ribosome distributions with respect to codon position along the length of the mRNA leads to polysome self-organization that drives translation rate to maximum levels (ii) the relative position of codons along the mRNA determines the optimal protein synthesis rate, and the translation rates of mRNAs are controlled by segments of sequence specific rate limiting codons, and (iii) minor codons play a role in optimizing translation rate, and their usage is important to the optimized, systemic allocation of ribosomes in the translation of mRNAs throughout the cell.

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  • 09/19/2018
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