Information Transmission and Processing in G-Protein-Coupled-Receptor Complexes

TL;DR

The paper develops a nonequilibrium, first-principles description of GPCR switching, arguing that information processing in GPCR complexes is sustained by ATP/GTP-driven chemical flux and modulated by a free-energy difference between phosphorylated and dephosphorylated states. It introduces the Biological Ensemble, which predicts three quasistable switch configurations and four possible outputs (two bits) arising from ligand structure and cis/trans conformations, beyond traditional two-state models. Experimental impedance data with photoactive ligands validate the theory, showing distinct on/off and active/inactive modes controlled by ligand conformation and the energy landscape; a critical flux $\phi_c \approx 0.182$ marks regime transitions. The framework offers a generalizable lens for understanding nonequilibrium information processing in biological switches and provides a principled path to targeting GPCR signaling in pharmacology.

Abstract

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 defin 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.

Figures (7)

• Figure 1: Conceptual schematic of the experiment. Ligands in cis (Z) or trans (E) configurations bind to GPCRs, while electrical impedance across a cell layer monitors signaling activity. Two engineered ligands (28 and 30) reversibly switch between Z and E isomers under wavelength-specific light (blue: Z→E; red: E→Z). Each conformation induces a distinct GPCR state, yielding four input combinations, encoding up to two bits of information.
• Figure 2: Simple Molecular SwitchA. The 7-transmembrane GPCR is illustrated with blue cylinders representing the seven $\alpha$ helices that span the cell membrane. The extracellular ligand (orange) binds to the binding site of the GPCR inducing movement with the $\alpha$ helical bundles. The helices alter the conformation of the intracellular loops (thin black lines) of the GPCR complex. The intracellular portion of the complex has been separated for visibility. Two pathways may be activated, the $G_{\alpha}$ pathway (purple) and the $\beta$arr pathway (tan). The $G_{\alpha}$ subunit is a part of the G protein also composed of subunits $\beta$ and $\gamma$. The $\beta$arr pathway is composed of additional response pathways determined by phosphorylation sites on the C tail of the GPCR and intracellular loops that form a barcode that encodes signals for downstream processes. B. Picture of a single switch taken to be a PdPC. A GTPase switch operates in the same manner. The switch resides in a heat bath at temperature $T$. In addition to the thermal bath, the switch is a component of a flexible protein complex that can modify energy barriers in the switch. Here, $\Pr(d)$ and $\Pr(p)$ are the probabilities of finding the receptor to be dephosphorylated and phosphorylated, respectively, while $\Pr(p|d)$ and $\Pr(d|p)$ are the conditional probabilities of finding the receptor has transitioned between phosphorylated to dephosphorylated positions and vice versa. C. Here, $J_0= \Pr(p|d)\Pr(d) = \Pr(d|p)\Pr(p)$ is the steady-state probability flux among states. The flux is kept finite due to an external energy/entropy source. D. Three-state model: free receptor (f), phosphorylated (p), and dephosphorylated (d). The bound state $b$ is bound to the ligand but not the phosphate. The associated state $b$ has two internal states $d$ and $p$. These two states form the $G_{\alpha}$ switch. Ligand dissociation and association reaction rates are given by $k_-$ and $k_+$, respectively, and $L$ is the ligand concentration. The picture for a GTPase switch is similar. A G protein-GDP is bound to $\Pr(a)$ and the ligand through a ternary reaction. The on state occurs when GDP is replaced with GTP.
• Figure 3: The quasistable solutions for $\Pr(p)$ for the Biological Ensemble as a function of the chemical flux $J_0$ and change in free energy between two receptor states $\beta \Delta E =\beta (E_p-E_d)$. A. In the limit of very small flux, the solutions are (1) $\Pr(p) = 1,\; \Pr(d) = 1-\Pr(p)=0$ (blue), (2) $\Pr(d) =(1-\Pr(p)= 1,\; \Pr(p)=0$ (red), and (3) the intermediate solution ($0<\Pr(p)<1$). B.-F. The intermediate branch steepens as the chemical flux $J_0$ increases. G.-I. For high values of flux $J_0$, the intermediate branch becomes less steep. For fluxes less that the critical flux $\phi_c \approx 0.182$
• Figure 4: The “on” and “off” switch conformations are modeled as water buckets labeled on and off, where water levels represent the probability of each receptor state. Forward flow fills the on bucket, while reverse flow fills the off bucket. A pump, analogous to ATP/GTP-driven energy input, powers the cycle. The flow magnitude and state occupancy are regulated by an energy barrier, represented by the height of the return tube, which controls resistance to reverse flow.
• Figure 5: A. and B. Experimental Results C.-F. Schematic of Quasistable States. For Ligand 28, irradiation with wavelengths 340nm and 455 nm toggle the the system between the E/on (trans) and the Z/off (cis) states. For Ligand 30, irradiation with 340 nm and 528 nm toggles between active and inactive configurations.