Jones Roger D, Giacometti Achille, Jones Alan M
Department of Biology University of North Carolina at Chapel Hill Chapel Hill North Carolina 27514 USA.
Dipartimento di Scienze Molecolari e Nanosistemi Universit"'a Ca' Foscari Venezia 30123 Venezia Italy.
ArXiv. 2025 Aug 14:arXiv:2508.11039v1.
G-protein-coupled receptors (GPCRs) are central to cellular information processing, yet the physical principles governing their switching behavior remain incompletely understood. We present a first-principles theoretical framework, grounded in nonequilibrium thermodynamics, to describe GPCR switching as observed in light-controlled impedance assays. The model identifies two fundamental control parameters: (1) ATP/GTP-driven chemical flux through the receptor complex, and (2) the free-energy difference between phosphorylated and dephosphorylated switch states. Together, these parameters define the switch configuration. The model predicts that GPCRs can occupy one of three quasi-stable configurations, each corresponding to a local maximum in information transmission. Active states support chemical flux and exist in an "on" or "off" switch configuration, whereas inactive states lack flux, introducing a distinction absent in conventional phosphorylation models. The model takes two ligand-derived inputs: fixed structural features and inducible conformations (e.g. cis or trans). It shows that phosphatase activity, modeled as an energy barrier, chiefly governs "on"/"off" occupancy, whereas the kinase sustains flux without directly determining the switch configuration. Comparison with experimental data confirms the predicted existence of multiple quasi-stable states modulated by ligand conformation. Importantly, this framework generalizes beyond GPCRs to encompass a wider class of biological switching systems driven by nonequilibrium chemical flux.
G蛋白偶联受体（GPCRs）是细胞信息处理的核心，但支配其开关行为的物理原理仍未完全被理解。我们提出了一个基于非平衡热力学的第一性原理理论框架，以描述在光控阻抗测定中观察到的GPCR开关行为。该模型确定了两个基本控制参数：（1）通过受体复合物的ATP/GTP驱动的化学通量，以及（2）磷酸化和去磷酸化开关状态之间的自由能差。这些参数共同定义了开关配置。该模型预测，GPCRs可以占据三种准稳定配置之一，每种配置对应于信息传递中的一个局部最大值。活性状态支持化学通量，并以“开”或“关”的开关配置存在，而非活性状态缺乏通量，这在传统的磷酸化模型中不存在。该模型采用两种源自配体的输入：固定的结构特征和可诱导的构象（如顺式或反式）。结果表明，被建模为能量屏障的磷酸酶活性主要控制“开”/“关”占据情况，而激酶维持通量但不直接决定开关配置。与实验数据的比较证实了由配体构象调节的多个准稳定状态的预测存在。重要的是，这个框架不仅适用于GPCRs，还可以推广到更广泛的由非平衡化学通量驱动的生物开关系统。
