Jul 2026· Journal of Chemical Information and Modeling· Vol 66, pp. 8410 - 8422· 0 citations· 43 references
Computer ScienceMedicine
TL;DR
This study leverage over 1200 three-dimensional structures of G protein-coupled receptors (GPCRs) to demonstrate that residues at the interface between GPCR and its ligand or G protein contain a higher density of frustrated residues compared to other structural regions in the receptor.
Abstract
The folded structure of a protein is understood to be an optimal energy state. However, previous studies have shown that certain amino acid residue positions that play a critical role in protein function are often in a suboptimal energy state or “frustrated”. Here, we leverage over 1200 three-dimensional structures of G protein-coupled receptors (GPCRs) to demonstrate that residues at the interface between GPCR and its ligand or G protein contain a higher density of frustrated residues compared to other structural regions in the receptor. Likewise, the Gα subunit of the trimeric G proteins shows multiple clusters of highly frustrated residues on its surface that overlap with their effector protein (Gbγ, RGS, Adenylyl cyclase, Ric8) binding interfaces. Our study highlights the use of protein frustration as one of the multiple structural properties to identify protein–protein interfaces and for prospective prediction of potential ligand binding sites.
Understanding how allosteric modulators influence protein dynamics is essential for guiding drug design. This work analyses a total of 45 μs of classical molecular dynamics simulations for four class A G-protein-coupled receptors (GPCRs), namely the Complement C5a receptor (C5AR1), the Purinergic Receptor P2Y (P2RY1), and the Cannabinoid Receptors 1 and 2 (CNR1/CNR2). Protein dynamics is essential to detect the shallow extrahelical binding sites, such as the one found in P2RY1. Current methods for computing Allosteric Communication Networks (ACNs) produce complex outputs requiring expert interpretation. To address this, we focus on the shortest paths of information transfer between the orthosteric and G-protein binding sites in Class A GPCRs. Our retrospective analysis reveals state- and bias ligand-dependent residue interactions along these communication pathways. Furthermore, focusing on the predicted binding site of allosteric modulator EC21a at cannabinoid receptors, the ACN framework was used to prioritize two residues for mutational analysis that may contribute to allosteric communication.
S. Peter, G. Chalhoub, Peter J. McCormick et al.· Journal of Chemical Informat...· 0 citations
This study maps the landscape of GPCR classification and function by translating the majority of the GPCR structures into structure graphs and analyzing over 2 million structural contacts to capture key aspects of the structural communication within the GPCR superfamily with implications in drug discovery.
Sara Gentile, Angelo Felline, Sara Mazzali et al.· JACS Au· 0 citations
G protein-coupled receptors (GPCRs) regulate diverse physiological responses by engaging distinct heterotrimeric G proteins, yet the basis of Gα selectivity in promiscuous receptors remains unclear. Although ligand bias holds therapeutic promise, selectivity has been assumed to reside mainly in the ligand-binding site (LBS) or G protein interface (GPI). Here, we combine whole-receptor mutagenesis, functional Gα protein assays, molecular dynamics simulations, interpretable machine learning method, and Bayesian network modeling to identify residue networks governing Gαq/11 and Gα12/13 coupling and to define the molecular basis of G protein preference and promiscuity at two vasopressor GPCRs, the angiotensin II type 1 and prostaglandin F2α receptors. While residues within the LBS and GPI domains contribute to coupling efficiency and subtype discrimination, we find that long-range allosteric communication across the receptor, including from structurally unresolved domains, is the principal determinant of Gα protein preference and promiscuity. These allosteric pathways integrate multiple receptor domains, confer signaling robustness to mutation, and hierarchically govern coupling preferences. Our findings suggest that Gα protein selectivity is an allosterically encoded property of GPCRs and provide a conceptual framework for designing ligands and receptors with tailored Gα protein-biased signaling.
Tegvir S. Boora, Han-Yu Chen, Aaron Cho et al.· bioRxiv· 0 citations
ProtLID2.0 is presented, a residue-specific pharmacophore framework that generates coordinate-based interaction preferences from molecular dynamics simulations of single-residue probes at receptor interfaces and uses these preferences to score docked complexes and identify cognate ligands.
S. Grudman, Christopher Mcclain, A. Fiser· Journal of Chemical Informat...· 0 citations
The model provides a computationally efficient framework for studying conformational ensembles and assembly of proteins at bilayer–water interfaces and is validated against Wimley–White free energies of transfer of hydrophobic peptides and against an experimentally refined conformational ensemble of a flexible membrane receptor.
Riccardo Saltutti, G. Tesei· bioRxiv· 0 citations
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