{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T12:46:40Z","timestamp":1792586800684,"version":"4.5.0"},"reference-count":82,"publisher":"American Chemical Society (ACS)","issue":"39","license":[{"start":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T00:00:00Z","timestamp":1726704000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T00:00:00Z","timestamp":1726704000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T00:00:00Z","timestamp":1726704000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000165","name":"Division of Chemistry","doi-asserted-by":"publisher","award":["CHE-1944892"],"award-info":[{"award-number":["CHE-1944892"]}],"id":[{"id":"10.13039\/100000165","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000165","name":"Division of Chemistry","doi-asserted-by":"publisher","award":["CHE-2326678"],"award-info":[{"award-number":["CHE-2326678"]}],"id":[{"id":"10.13039\/100000165","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Membrane-embedded mechanosensitive (MS) proteins, including ion channels and G-protein coupled receptors (GPCRs), are essential for the transduction of external mechanical stimuli into biological signals. The angiotensin II type 1 (AT1) receptor plays many important roles in cardiovascular regulation and is associated with diseases such as hypertension and congestive heart failure. The membrane-mediated activation of the AT1 receptor is not well understood, despite this being one of the most widely studied GPCRs within the context of biased agonism. Here, we use extensive molecular dynamics (MD) simulations to characterize the effect of the local membrane environment on the activation of the AT1 receptor. We show that membrane thickness plays an important role in the stability of active and inactive states of the receptor, as well as the dynamic interchange between states. Furthermore, our simulation results show that membrane tension is effective in driving large-scale structural changes in the inactive state such as the outward movement of transmembrane helix 6 to stabilize intermediate active-like conformations. We conclude by comparing our simulation observations with AlphaFold 2 predictions, as a proxy to experimental structures, to provide a framework for how membrane mediated stimuli can facilitate activation of the AT1 receptor through the \u03b2-arrestin signaling pathway.<\/jats:p>","DOI":"10.1021\/acs.jpcb.4c03325","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T14:26:33Z","timestamp":1726755993000},"page":"9470-9481","source":"Crossref","is-referenced-by-count":7,"title":["Structural Rearrangement\nof the AT1 Receptor Modulated\nby Membrane Thickness and Tension"],"prefix":"10.1021","volume":"128","author":[{"given":"Bharat","family":"Poudel","sequence":"first","affiliation":[{"name":"Oregon State University , , , ,","place":["Corvallis, Oregon, United States, 97331"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1381-1649","authenticated-orcid":true,"given":"Juan M.","family":"Vanegas","sequence":"additional","affiliation":[{"name":"Oregon State University , , , ,","place":["Corvallis, Oregon, United States, 97331"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2024,9,19]]},"reference":[{"key":"2026081805161107900_cit1","doi-asserted-by":"publisher","first-page":"3075","DOI":"10.1242\/jcs.092353","article-title":"Molecular force transduction by ion channels: diversity and unifying\nprinciples","volume":"125","author":"Sukharev","year":"2012","journal-title":"J. Cell Sci."},{"key":"2026081805161107900_cit2","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1080\/01677063.2022.2097674","article-title":"The force-from-lipid\nprinciple and its origin, a \u2018what is\ntrue for E. coli is true for the elephant\u2019\nrefrain","volume":"36","author":"Martinac","year":"2022","journal-title":"J. Neurogenet."},{"key":"2026081805161107900_cit3","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1038\/s41586-020-2933-1","article-title":"Discoveries\nin structure and physiology\nof mechanically activated ion channels","volume":"587","author":"Kefauver","year":"2020","journal-title":"Nature"},{"key":"2026081805161107900_cit4","doi-asserted-by":"publisher","first-page":"4802","DOI":"10.1128\/JB.00576-12","article-title":"The MscS and MscL families\nof mechanosensitive channels\nact as microbial emergency release valves","volume":"194","author":"Booth","year":"2012","journal-title":"J.\nBacteriol."},{"key":"2026081805161107900_cit5","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1016\/j.str.2011.09.005","article-title":"Mechanosensitive channels: What can\nthey do and how do they do it?","volume":"19","author":"Haswell","year":"2011","journal-title":"Structure"},{"key":"2026081805161107900_cit6","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1126\/science.1213808","article-title":"Crystal structure of the human K2P\nTRAAK, a lipid-and mechano-sensitive K+ ion channel","volume":"335","author":"Brohawn","year":"2012","journal-title":"Science"},{"key":"2026081805161107900_cit7","doi-asserted-by":"publisher","first-page":"3614","DOI":"10.1073\/pnas.1320768111","article-title":"Mechanosensitivity is mediated directly by the lipid\nmembrane in TRAAK and TREK1 K+ channels","volume":"111","author":"Brohawn","year":"2014","journal-title":"P.\nNatl. Acad. Sci. USA"},{"key":"2026081805161107900_cit8","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1111\/nyas.12874","article-title":"How ion\nchannels sense mechanical force: Insights from mechanosensitive K2P\nchannels TRAAK, TREK1, and TREK2","volume":"1352","author":"Brohawn","year":"2015","journal-title":"Ann. N.Y.\nAcad. Sci."},{"key":"2026081805161107900_cit9","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1016\/j.celrep.2016.10.033","article-title":"Piezo1 channels\nare inherently mechanosensitive","volume":"17","author":"Syeda","year":"2016","journal-title":"Cell Rep"},{"key":"2026081805161107900_cit10","doi-asserted-by":"publisher","first-page":"10347","DOI":"10.1073\/pnas.1409233111","article-title":"Piezo1,\na mechanically activated ion channel, is required for vascular development\nin mice","volume":"111","author":"Ranade","year":"2014","journal-title":"P. Natl. Acad. Sci. USA"},{"key":"2026081805161107900_cit11","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1038\/nature13980","article-title":"Piezo2 is the major\ntransducer of mechanical forces for touch sensation in mice","volume":"516","author":"Ranade","year":"2014","journal-title":"Nature"},{"key":"2026081805161107900_cit12","doi-asserted-by":"publisher","first-page":"C1047","DOI":"10.1152\/ajpcell.00465.2021","article-title":"Translating the force\ue5f8mechano-sensing GPCRs","volume":"322","author":"Wilde","year":"2022","journal-title":"Am. J. Physiol.-Cell Ph."},{"key":"2026081805161107900_cit13","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/ncb1137","article-title":"Mechanical\nstress activates angiotensin II type 1 receptor\nwithout the involvement of angiotensin II","volume":"6","author":"Zou","year":"2004","journal-title":"Nat.\nCell Biol."},{"key":"2026081805161107900_cit14","doi-asserted-by":"publisher","first-page":"28271","DOI":"10.1074\/jbc.M114.585067","article-title":"Allosteric modulation\nof \u03b2-arrestin-biased angiotensin II Type 1\nreceptor signalling by membrane strecth","volume":"289","author":"Tang","year":"2014","journal-title":"J.\nBiol. Chem."},{"key":"2026081805161107900_cit15","doi-asserted-by":"publisher","first-page":"3586","DOI":"10.1002\/jcb.26552","article-title":"Mechano-sensation\nof the angiotension II type 1 receptor induces \u03b2-arrestin-biased signalling through G\u03b1i coupling","volume":"119","author":"Wang","year":"2018","journal-title":"J. Cell Biochem."},{"key":"2026081805161107900_cit16","doi-asserted-by":"publisher","first-page":"H1241","DOI":"10.1152\/ajpheart.00818.2011","article-title":"protein-mediated stretch reception","volume":"302","author":"Storch","year":"2012","journal-title":"Am. J. Physiol-Heart C."},{"key":"2026081805161107900_cit17","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1016\/j.devcel.2012.07.015","article-title":"Flow-Regulated Endothelial\nS1P Receptor-1 Signaling Sustains Vascular Development","volume":"23","author":"Jung","year":"2012","journal-title":"Developmental Cell"},{"key":"2026081805161107900_cit18","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.phrs.2018.05.009","article-title":"Shear stress sensitizes\nTRPV4 in\nendothelium-dependent vasodilatation","volume":"133","author":"Darby","year":"2018","journal-title":"Pharmacol.\nRes."},{"key":"2026081805161107900_cit19","doi-asserted-by":"publisher","first-page":"C1633","DOI":"10.1152\/ajpcell.00576.2005","article-title":"G Protein-coupled receptors serve\nas mechanosensors for fluid shear stress in neutrophils","volume":"290","author":"Makino","year":"2006","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"2026081805161107900_cit20","doi-asserted-by":"publisher","first-page":"15463","DOI":"10.1073\/pnas.0607224103","article-title":"G protein-coupled\nreceptors sense\nfluid shear stress in endothelial cells","volume":"103","author":"Chachisvilis","year":"2006","journal-title":"Proc.\nNat. Acad. Sci. USA"},{"key":"2026081805161107900_cit21","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1161\/HYPERTENSIONAHA.111.172080","article-title":"Dopamine receptor type 5 in primary cilia has dual\nchemo-and mechano-sensory roles","volume":"58","author":"Abdul-Majeed","year":"2011","journal-title":"Hypertension"},{"key":"2026081805161107900_cit22","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1093\/cvr\/cvn230","article-title":"Angiotensin II type-1 receptor activation\nin the adult heart causes blood pressure-independent hypertrophy and\ncardiac dysfunction","volume":"81","author":"Ainscough","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"2026081805161107900_cit23","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1016\/j.mcna.2009.02.014","article-title":"The renin angiotensin\naldosterone system in hypertension: Roles of insulin resistance and\noxidative stress","volume":"93","author":"Manrique","year":"2009","journal-title":"Med. Clin. North Am."},{"key":"2026081805161107900_cit24","doi-asserted-by":"publisher","first-page":"19087","DOI":"10.1073\/pnas.0602715103","article-title":"Angiotensinergic\nstimulation of vascular endothelium\nin mice causes hypotension, bradycardia, and attenuated angiotensin\nresponse","volume":"103","author":"Ramchandran","year":"2006","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"2026081805161107900_cit25","doi-asserted-by":"publisher","first-page":"R324","DOI":"10.1016\/j.cub.2018.02.027","article-title":"GPCR signaling:\nThe interplay of\nG\u03b1i and \u03b2-arrestin","volume":"28","author":"Dwivedi","year":"2018","journal-title":"Curr. 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Physiol."},{"key":"2026081805161107900_cit31","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1016\/j.bbamem.2006.09.024","article-title":"G protein-coupled receptor systems and their lipid\nenvironment in health disorders during aging","volume":"1768","author":"Alemany","year":"2007","journal-title":"BBA - Biomembranes"},{"key":"2026081805161107900_cit32","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/B978-0-12-408143-7.00018-9","article-title":"Lipid-dependent\nGPCR\ndimerization","volume":"117","author":"Goddard","year":"2013","journal-title":"Methods Cell Biol."},{"key":"2026081805161107900_cit33","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/S0304-4157(98)00017-3","article-title":"Hydrophobic\nmismatch between proteins and lipids in membranes","volume":"1376","author":"Killian","year":"1998","journal-title":"BBA Rev. Biomembr."},{"key":"2026081805161107900_cit34","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1016\/j.bbamem.2006.09.001","article-title":"Lipid\u2013protein\ninteractions in GPCR-associated signaling","volume":"1768","author":"Escriba\u0301","year":"2007","journal-title":"BBA\n- Biomembranes"},{"key":"2026081805161107900_cit35","doi-asserted-by":"publisher","first-page":"2889","DOI":"10.1016\/j.bbamem.2015.08.004","article-title":"Lipid modulation of early G protein-coupled\nreceptor signalling events","volume":"1848","author":"Dijkman","year":"2015","journal-title":"BBA - Biomembranes"},{"key":"2026081805161107900_cit36","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1038\/s41589-023-01385-4","article-title":"Molecular mechanism\nof GPCR spatial organization at the plasma membrane","volume":"20","author":"Kockelkoren","year":"2024","journal-title":"Nat. Chem. Biol."},{"key":"2026081805161107900_cit37","doi-asserted-by":"publisher","first-page":"4464","DOI":"10.1529\/biophysj.106.082776","article-title":"Curvature\nand Hydrophobic\nForces Drive Oligomerizatonion and Modulate Activity of Rhodopsin\nin Membranes","volume":"91","author":"Botelho","year":"2006","journal-title":"Biophys. J."},{"key":"2026081805161107900_cit38","doi-asserted-by":"publisher","first-page":"12465","DOI":"10.1021\/ja803599x","article-title":"Lipid-Rhodopsin Hydrophobic\nmismatch alters Rhodopsin Helical content","volume":"130","author":"Soubias","year":"2008","journal-title":"J.\nAm. Chem. Soc."},{"key":"2026081805161107900_cit39","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1016\/j.bpj.2015.01.006","article-title":"Rhodopsin\/Lipid Hydrophobic\nMatching-Rhodopsin Oligomerization and Function","volume":"108","author":"Soubias","year":"2015","journal-title":"Biophys. J."},{"key":"2026081805161107900_cit40","doi-asserted-by":"publisher","first-page":"3938","DOI":"10.1038\/s41467-021-23756-y","article-title":"Allosteric modulation\nof ghrelin receptor signaling by lipids","volume":"12","author":"Damian","year":"2021","journal-title":"Nat.\nCommun."},{"key":"2026081805161107900_cit41","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1038\/s41589-020-0529-6","article-title":"Plasma membranes\nare asymmetric in lipid unsaturation, packing and protein shape","volume":"16","author":"Lorent","year":"2020","journal-title":"Nat. Chem. Biol."},{"key":"2026081805161107900_cit42","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1042\/ETLS20220084","article-title":"Elastic and\nthermodynamic\nconsequences of lipid membrane asymmetry","volume":"7","author":"Foley","year":"2023","journal-title":"Emerg.\nTop. Life Sci."},{"key":"2026081805161107900_cit43","doi-asserted-by":"publisher","first-page":"102832","DOI":"10.1016\/j.sbi.2024.102832","article-title":"Biomembranes\nbalance many types of leaflet asymmetries","volume":"87","author":"Deserno","year":"2024","journal-title":"Curr.\nOpin. Struc Biol."},{"key":"2026081805161107900_cit44","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1021\/ct4008926","article-title":"Importance of force\ndecomposition for local stress calculations in biomembrane molecular\nsimulations","volume":"10","author":"Vanegas","year":"2014","journal-title":"J. Chem. Theory Comput."},{"key":"2026081805161107900_cit45","doi-asserted-by":"publisher","first-page":"258102","DOI":"10.1103\/PhysRevLett.114.258102","article-title":"Examining the mechanical equilibrium\nof microscopic stresses in molecular simulations","volume":"114","author":"Torres-Sa\u0301nchez","year":"2015","journal-title":"Phys. Rev. Lett."},{"key":"2026081805161107900_cit46","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0113947","article-title":"Force transduction and lipid binding in MscL: A continuum-molecular\napproach","volume":"9","author":"Vanegas","year":"2014","journal-title":"PLoS ONE"},{"key":"2026081805161107900_cit47","doi-asserted-by":"publisher","first-page":"1159032","DOI":"10.3389\/fchem.2023.1159032","article-title":"Tight hydrophobic\ncore and flexible helices yield MscL with a high tension gating threshold\nand a membrane area mechanical strain buffer","volume":"11","author":"Sharma","year":"2023","journal-title":"Front. Chem."},{"key":"2026081805161107900_cit48","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.bpj.2020.11.2274","article-title":"Mechanical\nActivation of MscL Revealed by a Locally Distributed Tension Molecular\nDynamics Approach","volume":"120","author":"Rajeshwar T.","year":"2021","journal-title":"Biophys. J."},{"key":"2026081805161107900_cit49","doi-asserted-by":"publisher","first-page":"4690","DOI":"10.1038\/s41467-023-40433-4","article-title":"Membrane mediated mechanical stimuli\nproduces distinct active-like states in the AT1 receptor","volume":"14","author":"Poudel","year":"2023","journal-title":"Nat. Commun."},{"key":"2026081805161107900_cit50","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High\nperformance\nmolecular simulations through multi-level parallelism from laptops\nto supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"2026081805161107900_cit51","doi-asserted-by":"publisher","first-page":"3586","DOI":"10.1021\/jp973084f","article-title":"All-atom empirical potential\nfor molecular modeling\nand dynamics studies of proteins","volume":"102","author":"Mackerell","year":"1998","journal-title":"J. Phys. Chem.\nB"},{"key":"2026081805161107900_cit52","doi-asserted-by":"publisher","first-page":"3257","DOI":"10.1021\/ct300400x","article-title":"Optimization of the Additive CHARMM\nAll-Atom Protein Force Field Targeting Improved Sampling of the Backbone \u03d5, \u03c8 and Side-Chain \u03c71 and \u03c72 Dihedral Angles","volume":"8","author":"Best","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"2026081805161107900_cit53","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/nmeth.4067","article-title":"CHARMM36m:\nan improved force field for folded and intrinsically disordered proteins","volume":"14","author":"Huang","year":"2017","journal-title":"Nat. Methods"},{"key":"2026081805161107900_cit54","doi-asserted-by":"publisher","first-page":"7830","DOI":"10.1021\/jp101759q","article-title":"Update of the CHARMM All-Atom Additive Force Field\nfor Lipids: Validation on Six Lipid Types","volume":"114","author":"Klauda","year":"2010","journal-title":"J.\nPhys. Chem. B"},{"key":"2026081805161107900_cit55","doi-asserted-by":"publisher","first-page":"1526","DOI":"10.1021\/jz200167q","article-title":"Development of the CHARMM Force Field for Lipids","volume":"2","author":"Pastor","year":"2011","journal-title":"J. Phys. Chem. Lett."},{"key":"2026081805161107900_cit56","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1016\/j.cell.2018.12.006","article-title":"Distinctive Activation Mechanism for Angiotensin Receptor\nRevealed by a Synthetic Nanobody","volume":"176","author":"Wingler","year":"2019","journal-title":"Cell"},{"key":"2026081805161107900_cit57","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1126\/science.aaz0326","article-title":"Molecular Mechanism of biased signalling\nin a prototypical G Protein-coupled receptor","volume":"367","author":"Suomivuori","year":"2020","journal-title":"Science"},{"key":"2026081805161107900_cit58","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/S1043-9471(05)80049-7","volume-title":"Receptor\nMolecular Biology","author":"Ballesteros","year":"1995"},{"key":"2026081805161107900_cit59","doi-asserted-by":"publisher","first-page":"5.6.1","DOI":"10.1002\/cpbi.3","article-title":"Comparative Protein Structure Modeling\nUsing MODELLER","volume":"54","author":"Webb","year":"2016","journal-title":"Curr. Protoc. Bioinform"},{"key":"2026081805161107900_cit60","first-page":"41","article-title":"Anton 2: Raising the\nBar for Performance and Programmability in a Special-Purpose Molecular\nDynamics Supercomputer","volume-title":"SC \u201914: Proceedings\nof the International Conference for High Performance Computing, Networking,\nStorage and Analysis","author":"Shaw","year":"2014"},{"key":"2026081805161107900_cit61","doi-asserted-by":"publisher","first-page":"164106","DOI":"10.1063\/1.4825247","article-title":"Accurate and efficient\nintegration for molecular dynamics simulations at constant temperature\nand pressure","volume":"139","author":"Lippert","year":"2013","journal-title":"J. Chem. Phys."},{"key":"2026081805161107900_cit62","doi-asserted-by":"publisher","first-page":"054101","DOI":"10.1063\/1.1839571","article-title":"Gaussian\nsplit Ewald: A fast Ewald mesh method for molecular simulation","volume":"122","author":"Shan","year":"2005","journal-title":"J. Chem. 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