mRNA translation and protein synthesis: an analysis of different modelling methodologies and a new PBN based approach.
mRNA translation and protein synthesis: an analysis of different modelling methodologies and a new PBN based approach.
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DOI：
10.1186/1752-0509-8-25
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发表时间：
2014-02-27
影响因子：
--
通讯作者：
Krishnan J
中科院分区：
文献类型：
--
作者：
Zhao YB;Krishnan J
mRNA翻译涉及多个核糖体在mRNA上的同时运动，并且在不同阶段也受到调节机制的影响。翻译可以用各种基于密码子的模型来描述，包括ODE、TASEP和Petri网模型。虽然这些模型已被广泛使用，但这些模型之间的重叠和差异以及每个模型的假设含义尚未得到系统的阐明。选择最合适的建模框架，以及在不同的上下文中开发粗粒度/细粒度模型的最合适的方法是不清楚的。我们系统地分析和比较了如何使用不同的建模方法来描述翻译。我们定义了各种基于统计等效密码子的仿真算法，并分析了更新规则在确定稳态中的重要性，这是一个经常被忽视的方面。然后提出了一种新的概率布尔网络（PBN）模型，该模型具有精确的数值解。该解与其他方法的数值模拟结果相匹配，并作为解析近似和模拟的补充工具。比较了各种基于密码子的模型的优点和局限性，并通过慢密码子、过早终止和反馈调节等实际生物复杂性的例子进行了说明。我们的研究表明，虽然不同的模型在许多情况下给出了大致相似的趋势，但在翻译速率对不同参数的依赖性方面也出现了重要的差异，并且可以清楚地看到。此外，更新规则影响稳态解。基于密码子的模型基于不同的抽象层次。我们的分析表明，理解翻译的多模型方法允许人们确定结论的哪些方面在建模方法的选择方面是稳健的，以及何时（以及为什么）可能出现重要差异。这种方法还允许对分析工具的最佳使用，当包含额外的复杂性或监管机制时，这一点尤其重要。这种方法可以为解剖翻译提供一个强大的平台，并为系统和合成生物学的应用提供改进的预测框架。
mRNA translation involves simultaneous movement of multiple ribosomes on the mRNA and is also subject to regulatory mechanisms at different stages. Translation can be described by various codon-based models, including ODE, TASEP, and Petri net models. Although such models have been extensively used, the overlap and differences between these models and the implications of the assumptions of each model has not been systematically elucidated. The selection of the most appropriate modelling framework, and the most appropriate way to develop coarse-grained/fine-grained models in different contexts is not clear. We systematically analyze and compare how different modelling methodologies can be used to describe translation. We define various statistically equivalent codon-based simulation algorithms and analyze the importance of the update rule in determining the steady state, an aspect often neglected. Then a novel probabilistic Boolean network (PBN) model is proposed for modelling translation, which enjoys an exact numerical solution. This solution matches those of numerical simulation from other methods and acts as a complementary tool to analytical approximations and simulations. The advantages and limitations of various codon-based models are compared, and illustrated by examples with real biological complexities such as slow codons, premature termination and feedback regulation. Our studies reveal that while different models gives broadly similiar trends in many cases, important differences also arise and can be clearly seen, in the dependence of the translation rate on different parameters. Furthermore, the update rule affects the steady state solution. The codon-based models are based on different levels of abstraction. Our analysis suggests that a multiple model approach to understanding translation allows one to ascertain which aspects of the conclusions are robust with respect to the choice of modelling methodology, and when (and why) important differences may arise. This approach also allows for an optimal use of analysis tools, which is especially important when additional complexities or regulatory mechanisms are included. This approach can provide a robust platform for dissecting translation, and results in an improved predictive framework for applications in systems and synthetic biology.
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影响因子：
6.1
作者：
Agirrezabala, Xabier;Frank, Joachim
通讯作者：
Frank, Joachim
DOI：
10.1099/mic.0.067975-0
发表时间：
2013-07
期刊：
Microbiology (Reading, England)
影响因子：
--
作者：
Arpino JAJ;Hancock EJ;Anderson J;Barahona M;Stan GV;Papachristodoulou A;Polizzi K
通讯作者：
Polizzi K
影响因子：
4.8
作者：
Bag, J
通讯作者：
Bag, J
影响因子：
14.9
作者：
ADAMSKI, FM;DONLY, BC;TATE, WP
通讯作者：
TATE, WP
DOI：
10.1073/pnas.84.12.4022
发表时间：
1987-06-01
影响因子：
11.1
作者：
BUTLER, JS;SPRINGER, M;GRUNBERGMANAGO, M
通讯作者：
GRUNBERGMANAGO, M