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While existing structures have revealed inactive and active conformations, the ligand-dependent conformational energy landscape governing PAR1 activation remains poorly understood. Here, we employed enhanced-sampling molecular dynamics simulations using the string method with swarms of trajectories to quantify how extracellular ligands and G-protein binding modulate PAR1 activation. Free-energy landscapes were computed for five receptor states (apo, tethered agonist, thrombin receptor-activating peptide (TRAP), vorapaxar (VPX), and VPX + Na+) using five transmembrane (TM) helix distance metrics as collective variables. In the apo state, PAR1 samples inactive, intermediate, and active-like conformations, indicating substantial intrinsic receptor flexibility. VPX increases the free energy of active conformations and restricts TM helix 5 and 6 rearrangements, while VPX + Na+ eliminates intermediate basins and stabilizes the inactive state. In contrast, the tethered agonist stabilizes the active state as the global minimum and promotes TM6 displacement of up to \u223c1 nm. The simulations reveal a continuous activation pathway linking extracellular ligand engagement to intracellular motifs, including the connector, DRF, intracellular loop 3 (ICL3), and KRK motifs, with intracellular chloride ion coordination contributing to inactive-state stabilization. G\u03b1q binding reduces TM6 flexibility and shifts the free-energy minimum toward more active-like conformations. Alanine mutagenesis and Gq-CASE BRET assays validate predicted roles of key residues in activation and G-protein coupling. Together, these results provide a detailed understanding of ligand- and transducer-dependent PAR1 signaling and inform the design of pathway-selective PAR1 modulators.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c01315","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T08:01:57Z","timestamp":1790150517000},"page":"12800-12815","source":"Crossref","is-referenced-by-count":1,"title":["Energy Landscape Sampling Reveals Ligand-Dependent\nStructural Dynamics of the Protease-Activated Receptor 1"],"prefix":"10.1021","volume":"66","author":[{"given":"Inken Kaja","family":"Schwerin","sequence":"first","affiliation":[{"name":"Leipzig University , , Bru\u0308derstra\u00dfe 34 , ,","place":["Leipzig, Germany, 04103"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0559-6160","authenticated-orcid":true,"given":"Shihai","family":"Jiang","sequence":"additional","affiliation":[{"name":"University Hospital Leipzig , , Paul-List-Stra\u00dfe 13-15 , ,","place":["Leipzig, Germany, 04103"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Sta\u0308ubert","sequence":"additional","affiliation":[{"name":"Leipzig University , , Johannisallee 30 , ,","place":["Leipzig, Germany, 04103"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berend","family":"Isermann","sequence":"additional","affiliation":[{"name":"University Hospital Leipzig , , Paul-List-Stra\u00dfe 13-15 , ,","place":["Leipzig, Germany, 04103"]},{"name":"Leipzig University , , ,","place":["Leipzig, Germany, 04103"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1799-346X","authenticated-orcid":true,"given":"Georg","family":"Ku\u0308nze","sequence":"additional","affiliation":[{"name":"Leipzig University , , Bru\u0308derstra\u00dfe 34 , ,","place":["Leipzig, Germany, 04103"]},{"name":"Leipzig University , , ,","place":["Leipzig, Germany, 04107"]},{"name":"Leipzig University , , ,","place":["Leipzig, Germany, 04105"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"issue":"9","key":"2026101208074181000_cit1","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/nrm908","article-title":"Seven-Transmembrane\nReceptors","volume":"3","author":"Pierce","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"issue":"1","key":"2026101208074181000_cit2","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.cell.2017.11.033","article-title":"Pharmacogenomics\nof GPCR Drug Targets","volume":"172","author":"Hauser","year":"2018","journal-title":"Cell"},{"issue":"10","key":"2026101208074181000_cit3","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1161\/CIRCULATIONAHA.105.574830","article-title":"Protease-Activated\nReceptors in Cardiovascular\nDiseases","volume":"114","author":"Leger","year":"2006","journal-title":"Circulation"},{"issue":"8","key":"2026101208074181000_cit4","doi-asserted-by":"publisher","first-page":"1800","DOI":"10.1111\/j.1538-7836.2005.01377.x","article-title":"Protease-activated\nReceptors in Hemostasis, Thrombosis and Vascular Biology","volume":"3","author":"Coughlin","year":"2005","journal-title":"J. Thromb. Haemost."},{"issue":"1","key":"2026101208074181000_cit5","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s12959-019-0194-8","article-title":"Protease-Activated\nReceptors (PARs): Mechanisms of\nAction and Potential Therapeutic Modulators in PAR-Driven Inflammatory\nDiseases","volume":"17","author":"Heuberger","year":"2019","journal-title":"Thrombosis J."},{"issue":"6","key":"2026101208074181000_cit6","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1172\/JCI6042","article-title":"Protease-Activated\nReceptors 1 and 4 Mediate Activation of Human Platelets by Thrombin","volume":"103","author":"Kahn","year":"1999","journal-title":"J. Clin. Invest."},{"issue":"6801","key":"2026101208074181000_cit7","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1038\/35025229","article-title":"Thrombin\nSignalling and Protease-Activated Receptors","volume":"407","author":"Coughlin","year":"2000","journal-title":"Nature"},{"issue":"10","key":"2026101208074181000_cit8","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1161\/ATVBAHA.117.310068","article-title":"Protease-Activated\nReceptor-1 Signaling","volume":"37","author":"Flaumenhaft","year":"2017","journal-title":"Arterioscler. Thromb.\nVasc. Biol."},{"issue":"8","key":"2026101208074181000_cit9","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1016\/j.tips.2017.05.001","article-title":"Targeting PAR1: Now What?","volume":"38","author":"Flaumenhaft","year":"2017","journal-title":"Trends\nPharmacol. Sci."},{"issue":"8","key":"2026101208074181000_cit10","doi-asserted-by":"publisher","first-page":"2237","DOI":"10.3390\/ijms19082237","article-title":"Protease-Activated Receptor 1 as\nTherapeutic Target\nin Breast, Lung, and Ovarian Cancer: Pepducin Approach","volume":"19","author":"Covic","year":"2018","journal-title":"Int. J. Mol. Sci."},{"issue":"1","key":"2026101208074181000_cit11","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1161\/ATVBAHA.115.306777","article-title":"Cell-Penetrating\nPepducin Therapy Targeting PAR1 in Subjects With Coronary Artery Disease","volume":"36","author":"Gurbel","year":"2016","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"issue":"22","key":"2026101208074181000_cit12","doi-asserted-by":"publisher","first-page":"2675","DOI":"10.1182\/blood.2023019775","article-title":"Targeting Biased Signaling\nby PAR1: Function and Molecular\nMechanism of Parmodulins","volume":"141","author":"Ku\u0308nze","year":"2023","journal-title":"Blood"},{"issue":"9","key":"2026101208074181000_cit13","doi-asserted-by":"publisher","first-page":"2514","DOI":"10.1016\/j.bmc.2018.04.016","article-title":"Characterization\nof Protease-Activated\nReceptor (PAR) Ligands: Parmodulins Are Reversible Allosteric Inhibitors\nof PAR1-Driven Calcium Mobilization in Endothelial Cells","volume":"26","author":"Gandhi","year":"2018","journal-title":"Bioorgan Med. Chem."},{"issue":"17","key":"2026101208074181000_cit14","doi-asserted-by":"publisher","first-page":"3788","DOI":"10.1016\/j.bmc.2019.06.043","article-title":"The Parmodulin NRD-21 Is an Allosteric Inhibitor of\nPAR1 Gq Signaling with Improved Anti-Inflammatory Activity and Stability","volume":"27","author":"Gandhi","year":"2019","journal-title":"Bioorgan Med. Chem."},{"issue":"7429","key":"2026101208074181000_cit15","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/nature11701","article-title":"High-Resolution\nCrystal Structure of Human Protease-Activated Receptor 1","volume":"492","author":"Zhang","year":"2012","journal-title":"Nature"},{"issue":"D1","key":"2026101208074181000_cit16","doi-asserted-by":"publisher","first-page":"D395","DOI":"10.1093\/nar\/gkac1013","article-title":"GPCRdb in 2023: State-Specific Structure\nModels Using AlphaFold2 and New Ligand Resources","volume":"51","author":"Pa\u0301ndy-Szekeres","year":"2023","journal-title":"Nucleic Acids Res."},{"issue":"10","key":"2026101208074181000_cit17","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1038\/s41422-024-00997-2","article-title":"Structural\nBasis of Tethered Agonism and G Protein Coupling of Protease-Activated\nReceptors","volume":"34","author":"Guo","year":"2024","journal-title":"Cell Res."},{"issue":"8","key":"2026101208074181000_cit18","doi-asserted-by":"publisher","first-page":"2461","DOI":"10.1111\/febs.15841","article-title":"The Role of\nStructural Dynamics in GPCR-Mediated Signaling","volume":"288","author":"Hilger","year":"2021","journal-title":"FEBS J."},{"issue":"17","key":"2026101208074181000_cit19","doi-asserted-by":"publisher","first-page":"4237","DOI":"10.3390\/ijms20174237","article-title":"Recent\nInsights from Molecular Dynamics\nSimulations for G Protein-Coupled Receptor Drug Discovery","volume":"20","author":"Zou","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"2026101208074181000_cit20","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/bs.apcsb.2021.11.001","article-title":"Development\nof Enhanced Conformational Sampling Methods to Probe the Activation\nLandscape of GPCRs","volume-title":"Advances in Protein\nChemistry and Structural Biology","author":"Abrol","year":"2022"},{"key":"2026101208074181000_cit21","doi-asserted-by":"publisher","first-page":"1099715","DOI":"10.3389\/fendo.2022.1099715","article-title":"Metadynamics Simulations\nLeveraged\nby Statistical Analyses and Artificial Intelligence-Based Tools to\nInform the Discovery of G Protein-Coupled Receptor Ligands","volume":"13","author":"Salas-Estrada","year":"2022","journal-title":"Front. Endocrinol."},{"issue":"46","key":"2026101208074181000_cit22","doi-asserted-by":"publisher","first-page":"18684","DOI":"10.1073\/pnas.1110499108","article-title":"Activation Mechanism of the \u03922-Adrenergic\nReceptor","volume":"108","author":"Dror","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"23","key":"2026101208074181000_cit23","doi-asserted-by":"publisher","first-page":"8749","DOI":"10.1021\/ja404391q","article-title":"Ligand-Dependent\nActivation and Deactivation of the Human Adenosine A2A Receptor","volume":"135","author":"Li","year":"2013","journal-title":"J. Am. Chem. Soc."},{"issue":"34","key":"2026101208074181000_cit24","doi-asserted-by":"publisher","first-page":"7558","DOI":"10.1021\/acs.jpca.1c04110","article-title":"String Method\nwith Swarms-of-Trajectories, Mean Drifts, Lag Time, and Committor","volume":"125","author":"Roux","year":"2021","journal-title":"J. Phys. Chem. A"},{"issue":"3","key":"2026101208074181000_cit25","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1021\/acs.jctc.1c01049","article-title":"A Companion\nGuide to\nthe String Method with Swarms of Trajectories: Characterization, Performance,\nand Pitfalls","volume":"18","author":"Chen","year":"2022","journal-title":"J. Chem. Theory Comput."},{"key":"2026101208074181000_cit26","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.60715","article-title":"Identification\nof Ligand-Specific\nG Protein-Coupled Receptor States and Prediction of Downstream Efficacy\nvia Data-Driven Modeling","volume":"10","author":"Fleetwood","year":"2021","journal-title":"eLife"},{"issue":"6091","key":"2026101208074181000_cit27","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1126\/science.1219218","article-title":"Structural Basis\nfor Allosteric Regulation of GPCRs by Sodium Ions","volume":"337","author":"Liu","year":"2012","journal-title":"Science"},{"issue":"7","key":"2026101208074181000_cit28","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1021\/acs.biochem.9b00842","article-title":"Energy Landscapes\nReveal Agonist Control of G Protein-Coupled Receptor Activation via\nMicroswitches","volume":"59","author":"Fleetwood","year":"2020","journal-title":"Biochemistry"},{"issue":"21","key":"2026101208074181000_cit29","doi-asserted-by":"publisher","first-page":"E4158","DOI":"10.1073\/pnas.1617567114","article-title":"String\nMethod Solution of the Gating\nPathways for a Pentameric Ligand-Gated Ion Channel","volume":"114","author":"Lev","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"9","key":"2026101208074181000_cit30","doi-asserted-by":"publisher","first-page":"3938","DOI":"10.1021\/acs.jcim.9b00604","article-title":"Universal Activation\nIndex for Class\nA GPCRs","volume":"59","author":"Ibrahim","year":"2019","journal-title":"J. Chem. Inf. Model."},{"issue":"26","key":"2026101208074181000_cit31","doi-asserted-by":"publisher","first-page":"25048","DOI":"10.1074\/jbc.M414090200","article-title":"Functional Selectivity\nof G Protein Signaling by Agonist\nPeptides and Thrombin for the Protease-Activated Receptor-1","volume":"280","author":"McLaughlin","year":"2005","journal-title":"J. Biol. Chem."},{"issue":"4","key":"2026101208074181000_cit32","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1124\/pr.119.017863","article-title":"Harnessing Ion-Binding\nSites for GPCR Pharmacology","volume":"71","author":"Zarzycka","year":"2019","journal-title":"Pharmacol. Rev."},{"issue":"23","key":"2026101208074181000_cit33","doi-asserted-by":"publisher","first-page":"9501","DOI":"10.1073\/pnas.0811437106","article-title":"The Effect\nof Ligand Efficacy on the Formation and Stability of a GPCR-G Protein\nComplex","volume":"106","author":"Yao","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"7610","key":"2026101208074181000_cit34","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1038\/nature18324","article-title":"Allosteric\nCoupling\nfrom G Protein to the Agonist-Binding Pocket in GPCRs","volume":"535","author":"DeVree","year":"2016","journal-title":"Nature"},{"issue":"1","key":"2026101208074181000_cit35","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1021\/acs.chemrev.6b00177","article-title":"GPCR Dynamics: Structures in Motion","volume":"117","author":"Latorraca","year":"2017","journal-title":"Chem. 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U.S.A."},{"issue":"42","key":"2026101208074181000_cit39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2203702119","article-title":"The Full Activation Mechanism of\nthe Adenosine A1 Receptor Revealed by GaMD and Su-GaMD Simulations","volume":"119","author":"Li","year":"2022","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"699","key":"2026101208074181000_cit40","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abf1653","article-title":"Quantitative Assessment\nof Constitutive\nG Protein\u2013Coupled Receptor Activity with BRET-Based G Protein\nBiosensors","volume":"14","author":"Schihada","year":"2021","journal-title":"Sci. Signal"},{"issue":"2","key":"2026101208074181000_cit41","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1021\/ct100578z","article-title":"PROPKA3: Consistent Treatment of\nInternal and Surface\nResidues in Empirical pKa Predictions","volume":"7","author":"Olsson","year":"2011","journal-title":"J. Chem.\nTheory Comput."},{"issue":"46","key":"2026101208074181000_cit42","doi-asserted-by":"publisher","first-page":"7283","DOI":"10.1021\/bi5008723","article-title":"Insights into\nthe Role of Asp792.50\nin \u03922 Adrenergic Receptor Activation from Molecular Dynamics\nSimulations","volume":"53","author":"Ranganathan","year":"2014","journal-title":"Biochemistry"},{"issue":"10","key":"2026101208074181000_cit43","doi-asserted-by":"publisher","first-page":"2911","DOI":"10.1021\/acs.jcim.3c00380","article-title":"Machine Learning-Based Modeling of Olfactory Receptors\nin Their Inactive State: Human OR51E2 as a Case Study","volume":"63","author":"Alfonso-Prieto","year":"2023","journal-title":"J. Chem. Inf. Model."},{"key":"2026101208074181000_cit44","doi-asserted-by":"publisher","first-page":"2021.10.04.463034","DOI":"10.1101\/2021.10.04.463034","article-title":"Protein Complex Prediction with AlphaFold-Multimer","author":"Evans","year":"2021","journal-title":"bioRxiv"},{"issue":"11","key":"2026101208074181000_cit45","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A web-based graphical\nuser interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"issue":"27","key":"2026101208074181000_cit46","doi-asserted-by":"publisher","first-page":"1997","DOI":"10.1002\/jcc.23702","article-title":"CHARMM-GUI\nMembrane\nBuilder toward Realistic Biological Membrane Simulations","volume":"35","author":"Wu","year":"2014","journal-title":"J. Comput. Chem."},{"issue":"D1","key":"2026101208074181000_cit47","doi-asserted-by":"publisher","first-page":"D370","DOI":"10.1093\/nar\/gkr703","article-title":"OPM Database\nand PPM Web Server: Resources for Positioning of Proteins in Membranes","volume":"40","author":"Lomize","year":"2012","journal-title":"Nucleic Acids Res."},{"issue":"1","key":"2026101208074181000_cit48","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"},{"issue":"4","key":"2026101208074181000_cit49","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1002\/jcc.21367","article-title":"CHARMM General Force Field: A Force\nField for Drug-like Molecules Compatible with the CHARMM All-Atom\nAdditive Biological Force Fields","volume":"31","author":"Vanommeslaeghe","year":"2010","journal-title":"J. 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