Jain Aditi, Margaliot Michael, Gupta Arvind Kumar
Department of Mathematics, Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India.
School of Electrical Engineering and the Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv 69978, Israel.
J R Soc Interface. 2022 Mar;19(188):20220033. doi: 10.1098/rsif.2022.0033. Epub 2022 Mar 9.
We present a new theoretical framework for large-scale mRNA translation using a network of models called the ribosome flow model with Langmuir kinetics (RFMLK), interconnected via a pool of free ribosomes. The input to each RFMLK depends on the pool density, and it affects the initiation rate and potentially also the internal ribosome entry rates along each RFMLK. Ribosomes that detach from an RFMLK owing to termination or premature drop-off are fed back into the pool. We prove that the network always converges to a steady state, and study its sensitivity to variations in the parameters. For example, we show that if the drop-off rate at some site in some RFMLK is increased then the pool density increases and consequently the steady-state production rate in all the RFMLKs increases. Surprisingly, we also show that modifying a parameter of a certain RFMLK can lead to arbitrary effects on the densities along the modified RFMLK, depending on the parameters in the entire network. We conclude that the competition for shared resources generates an indirect and intricate web of mutual effects between the mRNA molecules that must be accounted for in any analysis of translation.
我们提出了一种用于大规模mRNA翻译的新理论框架，该框架使用了一个称为具有朗缪尔动力学的核糖体流动模型（RFMLK）的模型网络，这些模型通过一组游离核糖体相互连接。每个RFMLK的输入取决于核糖体库密度，并且它会影响起始速率，还可能影响沿每个RFMLK的内部核糖体进入速率。由于终止或过早脱落而从RFMLK脱离的核糖体被反馈回核糖体库。我们证明该网络总是收敛到一个稳态，并研究其对参数变化的敏感性。例如，我们表明，如果某个RFMLK中某个位点的脱落率增加，那么核糖体库密度就会增加，从而所有RFMLK中的稳态生产率都会增加。令人惊讶的是，我们还表明，根据整个网络中的参数，修改某个RFMLK的参数会对沿修改后的RFMLK的密度产生任意影响。我们得出结论，对共享资源的竞争在mRNA分子之间产生了一个间接且复杂的相互作用网络，在任何翻译分析中都必须考虑到这一点。
