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This study investigates the structural basis of ligand\u2010induced biased agonism within the context of the \u03b2<jats:sub>2<\/jats:sub>\u2010adrenergic receptor (\u03b2<jats:sub>2<\/jats:sub>\u2010AR). Atomistic molecular dynamics simulations were conducted for \u03b2<jats:sub>2<\/jats:sub>\u2010AR complexes with two stereoisomers of methoxynaphtyl fenoterol (MNFen), that is, compounds eliciting qualitatively different cellular responses. The simulations reveal distinct interaction patterns within the binding cavity, dependent on the stereoisomer. These changes propagate to the intracellular parts of the receptor, triggering various structural responses: the dynamic structure of the intracellular regions of the (R,R)\u2010MNFen complex more closely resembles the \u201cG<jats:sub>s<\/jats:sub>\u2010compatible\u201d and \u201c\u03b2\u2010arrestin\u2010compatible\u201d conformation of \u03b2<jats:sub>2<\/jats:sub>\u2010AR, while both stereoisomers maintain structural responses equidistant from the inactive conformation. These findings are confirmed by independent coarse\u2010grained simulations. In the context of deciphered molecular mechanisms, Trp313 plays a pivotal role, altering its orientation upon interactions with (R,R)\u2010MNFen, along with the Lys305\u2010Asp192 ionic bridge. This effect, accompanied by ligand interactions with residues on TM2, increases the strength of interactions within the extracellular region and the binding cavity, resulting in a slightly more open conformation and a minor (by ca. 0.2\u2009nm) increase in the distance between the TM5\u2013TM7, TM1\u2013TM6, TM6\u2013TM7, and TM1\u2013TM5 pairs. On the other hand, an even slighter decrease in the distance between the TM1\u2013TM4 and TM2\u2013TM4 pairs is observed.<\/jats:p>","DOI":"10.1002\/prot.26766","type":"journal-article","created":{"date-parts":[[2024,11,16]],"date-time":"2024-11-16T11:49:09Z","timestamp":1731757749000},"page":"728-744","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Unraveling the Structural Basis of Biased Agonism in the \u03b2<sub>2<\/sub>\u2010Adrenergic Receptor Through Molecular Dynamics Simulations"],"prefix":"10.1002","volume":"93","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1427-8188","authenticated-orcid":false,"given":"Wojciech","family":"Plazinski","sequence":"first","affiliation":[{"name":"Department of Biopharmacy Medical University of Lublin  Lublin Poland"},{"name":"Jerzy Haber Institute of Catalysis and Surface Chemistry Polish Academy of Sciences  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