Biophysical Society Thematic Meeting | Bucharest 2026

Biophysics of Membrane Reactions in Brian

Tuesday Speaker Abstracts

NETWORK MODEL-DRIVEN MOLECULAR SIMULATIONS REVEAL ALLOSTERIC DYNAMICS AND BIASED SIGNALLING IN CLASS C GPCRS Nida Yaren Yilmaz ; Özge Duman; Türkan Haliloglu; Bogaziçi University, Chemical Engineering and Polymer Research Center, Bebek, Istanbul, Turkey Metabotropic glutamate receptors, GABA B , and calcium-sensing receptors are brain-expressed Class C G protein–coupled receptors (GPCRs) that regulate neuronal excitability and synaptic plasticity through modulatory signalling. Understanding their conformational dynamics and signalling bias is essential for the development of therapeutics targeting central nervous system (CNS) disorders. These receptors possess a unique obligate dimeric architecture, in which a large extracellular Venus flytrap domain (VFTD) is connected to the transmembrane domain (TMD) via a cysteine-rich domain (CRD). Full receptor activation involves multi-step domain rearrangements occurring on millisecond timescales, making direct computational characterization of activation pathways particularly challenging. Here, we employ a hybrid computational framework that combines the Anisotropic Network Model (ANM) with Langevin Dynamics (LD), enabling intrinsic collective modes to guide transition pathways across multiple Class C GPCRs and allowing comparative analysis of shared and receptor-specific activation dynamics. We identify a conserved activation sequence involving VFTD closure, CRD compaction, and coordinated reorientation of the TMDs. These transitions are mediated by long range inter-subunit and intra-subunit couplings, indicating that activation is governed by global allosteric communication rather than localized molecular switches. Of particular relevance, hinge regions of the dominant dynamic modes that facilitate these transitions spatially overlap with key functional sites, including dimer interfaces, ligand-binding pockets, phospholipid interaction regions, and the G-protein coupling cavity. With the globally conserved and receptor-specific collective modes, this overlap suggests that functional sites positioned at dynamic control points can efficiently bias the global conformational ensemble toward specific signalling outcomes, providing a mechanistic basis for signalling bias in GPCRs. Taken together, our findings highlight hinge-associated allosteric sites in Class C GPCRs as promising targets for selectively modulating receptor function and inform the rational design of next-generation therapeutics for CNS disorders.

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