Controllability Analysis and Control Synthesis for the Ribosome Flow Model

Yoram Zarai, Michael Margaliot, Eduardo D. Sontag, Tamir Tuller

Research output: Contribution to journalArticlepeer-review

Abstract

The ribosomal density along different parts of the coding regions of the mRNA molecule affects various fundamental intracellular phenomena including: protein production rates, global ribosome allocation and organismal fitness, ribosomal drop off, co-translational protein folding, mRNA degradation, and more. Thus, regulating translation in order to obtain a desired ribosomal profile along the mRNA molecule is an important biological problem. We study this problem by using a dynamical model for mRNA translation, called the ribosome flow model (RFM). In the RFM, the mRNA molecule is modeled as an ordered chain of n sites. The RFM includes n state-variables describing the ribosomal density profile along the mRNA molecule, and the transition rates from each site to the next are controlled by n+1 positive constants. To study the problem of controlling the density profile, we consider some or all of the transition rates as time-varying controls. We consider the following problem: given an initial and a desired ribosomal density profile in the RFM, determine the time-varying values of the transition rates that steer the system to the desired density profile, if they exist. More specifically, we consider two control problems. In the first, all transition rates can be regulated separately, and the goal is to steer the ribosomal density profile and the protein production rate from a given initial value to a desired value. In the second problem, one or more transition rates are jointly regulated by a single scalar control, and the goal is to steer the production rate to a desired value within a certain set of feasible values. In the first case, we show that the system is controllable, i.e., the control is powerful enough to steer the system to any desired value in finite time, and provide simple closed-form expressions for constant positive control functions (or transition rates) that asymptotically steer the system to the desired value. In the second case, we show that the system is controllable, and provide a simple algorithm for determining the constant positive control value that asymptotically steers the system to the desired value. We discuss some of the biological implications of these results.

Original languageEnglish
Article number7932937
Pages (from-to)1351-1364
Number of pages14
JournalIEEE/ACM Transactions on Computational Biology and Bioinformatics
Volume15
Issue number4
DOIs
StatePublished - 1 Jul 2018

Keywords

  • Lie-algebra
  • Systems biology
  • accessibility
  • asymptotic controllability
  • control synthesis
  • control-affine systems
  • controllability
  • gene translation
  • ribosomal density profile
  • ribosome flow model
  • synthetic biology

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