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动力学图分析:一个用于解析计算生化系统稳态可观测量的Python库。

Kinetic Diagram Analysis: A Python Library for Calculating Steady-State Observables of Biochemical Systems Analytically.

作者信息

Carl Awtrey Nikolaus, Beckstein Oliver

机构信息

Department of Physics, Arizona State University, Tempe AZ, USA.

Center for Biological Physics, Arizona State University, Tempe AZ, USA.

出版信息

bioRxiv. 2024 Aug 4:2024.05.27.596119. doi: 10.1101/2024.05.27.596119.

Abstract

Kinetic diagrams are commonly used to represent biochemical systems in order to study phenomena such as free energy transduction and ion selectivity. While numerical methods are commonly used to analyze such kinetic networks, the diagram method by King, Altman and Hill makes it possible to construct exact algebraic expressions for steady-state observables in terms of the rate constants of the kinetic diagram. However, manually obtaining these expressions becomes infeasible for models of even modest complexity as the number of the required intermediate diagrams grows with the factorial of the number of states in the diagram. We developed (KDA), a Python library that programmatically generates the relevant diagrams and expressions from a user-defined kinetic diagram. KDA outputs symbolic expressions for state probabilities and cycle fluxes at steady-state that can be symbolically manipulated and evaluated to quantify macroscopic system observables. We demonstrate the KDA approach for examples drawn from the biophysics of active secondary transmembrane transporters. For a generic 6-state antiporter model, we show how the introduction of a single leakage transition reduces transport efficiency by quantifying substrate turnover. We apply KDA to a real-world example, the 8-state free exchange model of the small multidrug resistance transporter EmrE of Hussey et al ( (2020), e201912437), where a change in transporter phenotype is achieved by biasing two different subsets of kinetic rates: alternating access and substrate unbinding rates. KDA is made available as open source software under the GNU General Public License version 3.

摘要

动力学图通常用于表示生化系统,以便研究诸如自由能转导和离子选择性等现象。虽然数值方法通常用于分析此类动力学网络,但金(King)、奥特曼(Altman)和希尔(Hill)提出的图方法使得能够根据动力学图的速率常数为稳态可观测量构建精确的代数表达式。然而,对于即使是中等复杂度的模型,手动获取这些表达式也变得不可行,因为所需中间图的数量会随着图中状态数量的阶乘增长。我们开发了一个名为动力学图分析器(Kinetic Diagram Analyzer,KDA)的Python库,它可以根据用户定义的动力学图以编程方式生成相关的图和表达式。KDA输出稳态下状态概率和循环通量的符号表达式,这些表达式可以进行符号操作和求值,以量化宏观系统的可观测量。我们通过从活性次级跨膜转运蛋白的生物物理学中选取的例子展示了KDA方法。对于一个通用的6态反向转运体模型,我们展示了如何通过量化底物周转来引入单个泄漏转变从而降低转运效率。我们将KDA应用于一个实际例子,即赫西等人(Hussey et al,(2020),e201912437)的小多药耐药转运蛋白EmrE的8态自由交换模型,其中通过偏向两个不同的动力学速率子集(交替访问和底物解离速率)来实现转运体表型的改变。KDA作为开源软件根据GNU通用公共许可证第3版提供。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdd8/11298961/f0a374c77cde/nihpp-2024.05.27.596119v2-f0001.jpg

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