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The lower energy of the inactive state under basal conditions, as well as the transient nature of intermediates have impeded the characterization of GPCR\u2019s activation mechanisms at full-atomic scale. In this study, we generate in silico thousands of full-atomic, continuous pathways, visualizing the complete activation mechanism of a broadly studied GPCR, the \u03b22 adrenergic receptor. To this aim, we adopted a minimalist model that prioritizes the intrinsic dynamics of the receptor, combined with weighted ensemble-enhanced molecular dynamics (WEMD) simulations. Clustering analysis of the generated trajectories reveals distinct classes of activation, including an off-pathway transition, and conformational switches that enable activation. Simulations of two mutants, D1303.49A and E2686.30A, show their high propensity to get activated, consistent with experimental observations. Overall, WEMD emerges as a promising method for navigating GPCR\u2019s conformational landscape and predicting the effects of mutations, well beyond the reach of conventional simulations.<\/jats:p>","DOI":"10.1021\/acsphyschemau.6c00090","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T20:39:10Z","timestamp":1788208750000},"page":"1283-1298","source":"Crossref","is-referenced-by-count":0,"title":["A Minimalist\nModel for Navigating Conformational Landscape\nUncovers the Activation Mechanism of \u03b22-Adrenergic\nReceptor"],"prefix":"10.1021","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8032-6861","authenticated-orcid":true,"given":"Satyaki","family":"Saha","sequence":"first","affiliation":[{"name":"Stony Brook University , , , ,","place":["New York, Stony Brook, United States, 11794"]},{"name":"Stony Brook University , , , ,","place":["New York, Stony Brook, United States, 11794"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony T.","family":"Bogetti","sequence":"additional","affiliation":[{"name":"Stony Brook University , , , ,","place":["New York, Stony Brook, United States, 11794"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9959-4176","authenticated-orcid":true,"given":"Ivet","family":"Bahar","sequence":"additional","affiliation":[{"name":"Stony Brook University , , , ,","place":["New York, Stony Brook, United States, 11794"]},{"name":"Stony Brook University , , , ,","place":["New York, Stony Brook, United States, 11794"]},{"name":"Stony Brook University , , , ,","place":["New York, Stony Brook, United States, 11794"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"2026092310063650100_cit1","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1161\/CIRCRESAHA.124.323067","article-title":"G Protein-Coupled\nReceptors: A Century of Research\nand Discovery","volume":"135","author":"Liu","year":"2024","journal-title":"Circ. 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