具有两到五个结合位点的受体平衡常数的可识别性。

IF 3.3 2区 医学 Q1 PHYSIOLOGY
Journal of General Physiology Pub Date : 2023-12-04 Epub Date: 2023-10-26 DOI:10.1085/jgp.202313423
Klaus Benndorf, Eckhard Schulz
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引用次数: 0

摘要

配体门控离子通道(LGIC)是含有两到五个配体结合位点的规则低聚物。在同聚体或异聚体LGIC中,配体结合引起的激活过程都不完全清楚。在这里,我们在理论上表明,对于具有两到五个结合位点的LGIC,可以相当详细地确定通道激活时的协同性。我们策略的主要要求是通道中定义数量的结合位点,这可以通过串联、所有结合位点的系统突变以及所有浓度-激活关系(CAR)与相应的密切耦合马尔可夫状态模型的全局拟合来实现。我们利用将这些状态模型转换为维度为2、3、4和5的立方体的优势。我们表明,这些LGIC的最大可能CAR数量分别指定了所有7、13、23和41个独立的模型参数,这些参数直接提供了各自方案中的所有平衡常数。此外,使用随机变化的缩放酉起始向量的拟合能够确定所有参数,而没有由特定起始向量施加的任何偏差。对具有2-5个结合位点的模型的分析结果的比较表明,对于具有5个结合位点和41个参数的情况,参数的可识别性最好。我们的策略可用于分析其他LGIC的实验数据,并可能适用于电压门控离子通道和代谢型受体。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Identifiability of equilibrium constants for receptors with two to five binding sites.

Ligand-gated ion channels (LGICs) are regularly oligomers containing between two and five binding sites for ligands. Neither in homomeric nor heteromeric LGICs the activation process evoked by the ligand binding is fully understood. Here, we show on theoretical grounds that for LGICs with two to five binding sites, the cooperativity upon channel activation can be determined in considerable detail. The main requirements for our strategy are a defined number of binding sites in a channel, which can be achieved by concatenation, a systematic mutation of all binding sites and a global fit of all concentration-activation relationships (CARs) with corresponding intimately coupled Markovian state models. We take advantage of translating these state models to cubes with dimensions 2, 3, 4, and 5. We show that the maximum possible number of CARs for these LGICs specify all 7, 13, 23, and 41 independent model parameters, respectively, which directly provide all equilibrium constants within the respective schemes. Moreover, a fit that uses stochastically varied scaled unitary start vectors enables the determination of all parameters, without any bias imposed by specific start vectors. A comparison of the outcome of the analyses for the models with 2 to 5 binding sites showed that the identifiability of the parameters is best for a case with 5 binding sites and 41 parameters. Our strategy can be used to analyze experimental data of other LGICs and may be applicable to voltage-gated ion channels and metabotropic receptors.

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来源期刊
CiteScore
6.00
自引率
10.50%
发文量
88
审稿时长
6-12 weeks
期刊介绍: General physiology is the study of biological mechanisms through analytical investigations, which decipher the molecular and cellular mechanisms underlying biological function at all levels of organization. The mission of Journal of General Physiology (JGP) is to publish mechanistic and quantitative molecular and cellular physiology of the highest quality, to provide a best-in-class author experience, and to nurture future generations of independent researchers. The major emphasis is on physiological problems at the cellular and molecular level.
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