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Effects of Codon Distributions and tRNA Competition on Protein Translation

Hermioni Zouridis ^* and Vassily Hatzimanikatis 

^* Department of Chemical and Biological Engineering, McCormick School of Engineering and Applied Sciences, Northwestern University, Evanston, Illinois; and Laboratory of Computational Systems Biotechnology, École Polytechnique Fédérale de Lausanne, CH-1015, Lausanne, Switzerland

Correspondence: Address reprint requests to Vassily Hatzimanikatis, Tel.: 41-0-21-693-98-70; E-mail: vassily.hatzimanikatis{at}epfl.ch.

Translation is a central cellular process and the complexity of its mechanism necessitates mathematical frameworks to better understand system properties and make quantitative predictions. We have developed a gene sequence-specific mechanistic model for translation which accounts for all the elementary steps of translation elongation. Included in our model is the nonspecific binding of tRNAs to the ribosomal A site, and we find that the competitive, nonspecific binding of the tRNAs is the rate-limiting step in the elongation cycle for every codon. By introducing our model in terms of the Michaelis-Menten kinetic framework, we determine that these results are due to the tRNAs that do not recognize the ribosomal A site codon acting as competitive inhibitors to the tRNAs that do recognize the ribosomal A site codon. We present the results of a sensitivity analysis to determine the contribution of elongation cycle kinetic parameters of each codon on the overall translation rate, and observe that the translation rates of mRNAs are controlled by segments of rate-limiting codons that are sequence-specific. Along these lines, we find that the relative position of codons along the mRNA determines the optimal protein synthesis rate.