The structure of binding curves and practical identifiability of equilibrium ligand-binding parameters.
The structure of binding curves and practical identifiability of equilibrium ligand-binding parameters.
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DOI：
10.1085/jgp.201611703
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Aldrich RW
中科院分区：
文献类型：
--
作者：
Middendorf TR;Aldrich RW
在他们之前的论文中，Middendorf和Aldrich描述了一种方法来确定从激动剂结合模型估计的结合参数的准确性。在这里，他们提出了一种方法来确定是否可以从实验或噪声数据中准确估计绑定参数。在配体与蛋白质结合的研究中，一个关键但经常被忽视的问题是，从分析结合数据获得的参数是否具有实际可识别性（PI），即从拟合模型到噪声数据获得的估计是否准确和唯一。在这里，我们报告了一种评估和理解结合参数可识别性的一般方法，它提供了一个工具包，以帮助实验人员设计结合研究和分析结合数据。采用部分分式展开技术，将具有n个配体结合位点的蛋白质的结合曲线精确而唯一地分解为n个组分，每个组分具有单位点结合曲线的形式。PF分量曲线的关联常数作为n阶多项式的根，可以是实数，也可以是复数。我们证明了绑定参数可识别性与这些单位点关联常数之间的基本联系：如果常数都是实数且不同的，则所有绑定参数都是可识别的；否则，至少有些参数是不可识别的。该理论用于构建可识别性图，从中可以评估任何两个，三个或四个位点结合曲线的结合参数的实际可识别性。还给出了扩展方法以生成具有四个以上结合位点的蛋白质的可识别性图的说明。对可识别性图的进一步分析得出一个简单的规则，即只有当绑定曲线形状包含n个可分辨分量时，结构可识别的绑定参数的最大数目（在前一篇文章中显示为等于n）也将为PI。
In their preceding paper, Middendorf and Aldrich describe a method to determine the accuracy of binding parameters estimated from models of agonist binding. Here, they present an approach to determine whether binding parameters can be accurately estimated from experimental, or noisy, data. A critical but often overlooked question in the study of ligands binding to proteins is whether the parameters obtained from analyzing binding data are practically identifiable (PI), i.e., whether the estimates obtained from fitting models to noisy data are accurate and unique. Here we report a general approach to assess and understand binding parameter identifiability, which provides a toolkit to assist experimentalists in the design of binding studies and in the analysis of binding data. The partial fraction (PF) expansion technique is used to decompose binding curves for proteins with n ligand-binding sites exactly and uniquely into n components, each of which has the form of a one-site binding curve. The association constants of the PF component curves, being the roots of an n-th order polynomial, may be real or complex. We demonstrate a fundamental connection between binding parameter identifiability and the nature of these one-site association constants: all binding parameters are identifiable if the constants are all real and distinct; otherwise, at least some of the parameters are not identifiable. The theory is used to construct identifiability maps from which the practical identifiability of binding parameters for any two-, three-, or four-site binding curve can be assessed. Instructions for extending the method to generate identifiability maps for proteins with more than four binding sites are also given. Further analysis of the identifiability maps leads to the simple rule that the maximum number of structurally identifiable binding parameters (shown in the previous paper to be equal to n) will also be PI only if the binding curve line shape contains n resolved components.
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影响因子：
4.3
作者：
BELLMAN R;ASTROM K J
通讯作者：
ASTROM K J
影响因子：
5.8
作者：
Raue, A.;Kreutz, C.;Timmer, J.
通讯作者：
Timmer, J.
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作者：
SOLC, CK;ALDRICH, RW
通讯作者：
ALDRICH, RW
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作者：
Stefan MI;Edelstein SJ;Le Novère N
通讯作者：
Le Novère N
影响因子：
5.5
作者：
COLQUHOUN, D;OGDEN, DC
通讯作者：
OGDEN, DC