Modelling cellular protein synthesis : the complexity of ribosome traffic on mRNA chains

• Main Author: Ciandrini, Luca
• Published: University of Aberdeen 2012
• Subjects: 530
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.560890

In this thesis I study the last step of gene expression, namely mRNA translation, by means of approaches and quantitative methods borrowed from non-equilibrium statistical mechanics such as the totally asymmetric simple exclusion process (TASEP), the prototypic model of unidimensional transport. The flow of ribosomes along the mRNA chains is thus represented by a driven lattice gas in which, in order to provide an accurate description of the underlying biological process, I consider particles with a stepping dynamics that mimics the mechano-chemical cycle of the ribosomal machines. With this extension the system clearly shows new phenomenologies that I investigate both analytically and numerically. Moreover, in a genome scale application of the model, I determine and characterise traffic effects in real sequences, and crucially highlight their biological relevance in S.cerevisiae to understand the translational contribution to gene expression. The role of constrained resources, namely the finite number of ribosomes and its partitioning among the different mRNAs, is also studied in depth. The theory distinctly provides a tool to describe the competition for resources by different mRNAs; being the cell a complex system that continuously has to balance its costs and benefits, this is believed to play a central biological role. The developed method establishes a general framework to deal with several exclusion processes sharing the same finite pool of particles, and the theoretical results distinctly indicate the presence of a regime in which the amount of free particles is “buffered”. I finally demonstrate how the folding/unfolding dynamics of mRNA secondary structures influence the ribosomal flow, emphasising their regulatory role. In order to model the interaction between particles and the unidimensional lattice, I introduce the concept of dynamical defect, which describes the impact of conformational changes of the nucleotide chain. Remarkably, I observe a novel regime characterised by an intermittent particle flow.