Biophysical Society Thematic Meeting | Bucharest 2026

Biophysics of Membrane Reactions in Brian

Tuesday Speaker Abstracts

EXPLORING GPCR DYNAMICS AT SCALE USING MOLECULAR DYNAMICS SIMULATIONS Jana Selent Hospital del Mar Medical Research Institute (IMIM) & Pompeu Fabra University, Barcelona, Spain Recent advances in X-ray crystallography and cryogenic electron microscopy have enabled high resolution structural characterization of GPCRs in multiple functional states. However, GPCR signaling is intrinsically dynamic, and static structures alone cannot fully capture the conformational flexibility underlying receptor activation and ligand recognition. Here, we present the largest molecular dynamics (MD) simulation dataset to date for GPCRs, encompassing simulations for approximately 60% of currently available GPCR structures [1]. Systematic analysis of these simulations reveals widespread local “breathing” motions of the receptors occurring on nano- to microsecond timescales, enabling exploration of a rich ensemble of previously unobserved conformational states. Furthermore, we reveal that receptor flexibility significantly impacts the shape of allosteric drug binding sites, which frequently adopt partially or completely closed states in the absence of a molecular modulator. We demonstrate that exploring membrane lipid dynamics and their interaction with GPCRs is an efficient approach to expose such hidden allosteric sites and even lateral ligand entrance gateways. These new insights and the unprecedented dataset on novel conformations, allosteric sites and lateral entrance gates in GPCRs allows us to better understand the functionality of these receptors and opens new therapeutic avenues for drug-targeting strategies.[1] Aranda-García D et al. Large scale investigation of GPCR molecular dynamics data uncovers allosteric sites and lateral gateways. Nat Commun. 2025;16(1):2020. PMID: 40016203.

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