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GLP\u20101 receptor agonists (GLP\u20101RAs) have been developed to treat type 2 diabetes and promote weight loss. In this study, Gaussian accelerated molecular dynamics (GaMD) simulations, MM\u2010PBSA calculations, and conformational dynamic analyses were systematically employed to elucidate the binding mechanisms and dynamic stability of three representative agonists\u2014native GLP\u20101, semaglutide, and tirzepatide\u2014bound to the GLP\u20101R\u2010Gs membrane protein complex. Molecular docking and trajectory analyses revealed that ligand binding significantly stabilizes the overall receptor structure, triggering conformational shifts in the extracellular domain (ECD) and transmembrane domain (TMD), particularly inducing long\u2010range allosteric cross\u2010talk with the intracellular Gs protein to downstream signal transduction. Compared to GLP\u20101 and semaglutide, tirzepatide demonstrated distinct conformational shifts, superior structural compactness, and the higher binding affinity with a significantly more negative binding free energy. Furthermore, micro\u2010interfacial localization demonstrated that lipid bilayer interaction with basic and aromatic residues at the Zp interface synergistically stabilizes the active transmembrane conformation. These atomic\u2010level insights highlight the unique structural advantages of tirzepatide and provide a solid theoretical foundation for the novel rational design of next\u2010generation multi\u2010target peptide therapeutics.<\/jats:p>","DOI":"10.1002\/prot.70186","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T03:31:21Z","timestamp":1790911881000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interactions of Glucagon\u2010Like Peptide\u20101 Receptor Agonists With\n                    <scp>GLP<\/scp>\n                    \u2010\n                    <scp>1R<\/scp>\n                    \u2010\n                    <scp>Gs<\/scp>\n                    Complex: Insights From\n                    <scp>G<\/scp>\n                    aussian\u2010Accelerated Molecular 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