{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T19:06:52Z","timestamp":1774033612154,"version":"3.50.1"},"reference-count":52,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,2,26]],"date-time":"2022-02-26T00:00:00Z","timestamp":1645833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Interleukin-1 receptor type 1 (IL-1R1) is a key player in inflammation and immune responses. This receptor regulates IL-1 activity in two forms: as a membrane-bound form and as a soluble ectodomain. The details and differences between the conformational dynamics of the membrane-bound and the soluble IL-1R1 ectodomains (ECDs) remain largely elusive. Here, we study and compare the structural dynamics of the soluble and membrane-bound IL-1R1-ECDs using molecular dynamics (MD) simulations, focusing on the flexible interdomain linker of the ECD, as well as the spatial rearrangements between the Ig-like domains of the ECD. To explore the membrane-bound conformations, a full-length IL-1R1 structural model was developed and subjected to classical equilibrium MD. Comparative analysis of multiple MD trajectories of the soluble and the membrane-bound IL-1R1-ECDs reveals that (i) as somewhat expected, the extent of the visited \u201copen-to-closed\u201d transitional states differs significantly between the soluble and membrane-bound forms; (ii) the soluble form presents open-closed transitions, sampling a wider rotational motion between the Ig-like domains of the ECD, visiting closed and \u201ctwisted\u201d conformations in higher extent, whereas the membrane-bound form is characterized by more conformationally restricted states; (iii) interestingly, the backbone dihedral angles of residues Glu202, Glu203 and Asn204, located in the flexible linker, display the highest variations during the transition between discrete conformational states detected in IL-1R1, thus appearing to work as the \u201ccentral wheel of a clock\u2019s movement\u201d. The simulations and analyses presented in this contribution offer a deeper insight into the structure and dynamics of IL-1R1, which may be explored in a drug discovery setting.<\/jats:p>","DOI":"10.3390\/ijms23052599","type":"journal-article","created":{"date-parts":[[2022,2,27]],"date-time":"2022-02-27T20:47:17Z","timestamp":1645994837000},"page":"2599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Conformational Dynamics of the Soluble and Membrane-Bound Forms of Interleukin-1 Receptor Type-1: Insights into Linker Flexibility and Domain Orientation"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2760-6996","authenticated-orcid":false,"given":"Jo\u00e3o P.","family":"Lu\u00eds","sequence":"first","affiliation":[{"name":"Coimbra Chemistry Center\u2014Institute of Molecular Sciences (CQC-IMS), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9508-7035","authenticated-orcid":false,"given":"Ana I.","family":"Mata","sequence":"additional","affiliation":[{"name":"Coimbra Chemistry Center\u2014Institute of Molecular Sciences (CQC-IMS), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5994-9104","authenticated-orcid":false,"given":"Carlos J. V.","family":"Sim\u00f5es","sequence":"additional","affiliation":[{"name":"Coimbra Chemistry Center\u2014Institute of Molecular Sciences (CQC-IMS), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"},{"name":"BSIM Therapeutics, Instituto Pedro Nunes, 3030-199 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9128-2557","authenticated-orcid":false,"given":"Rui M. M.","family":"Brito","sequence":"additional","affiliation":[{"name":"Coimbra Chemistry Center\u2014Institute of Molecular Sciences (CQC-IMS), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"},{"name":"BSIM Therapeutics, Instituto Pedro Nunes, 3030-199 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nri2691","article-title":"The IL-1 family: Regulators of immunity","volume":"10","author":"Sims","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1111\/imr.12606","article-title":"The family of the interleukin-1 receptors","volume":"281","author":"Boraschi","year":"2018","journal-title":"Immunol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/nrd3800","article-title":"Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases","volume":"11","author":"Dinarello","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/j.immuni.2019.03.012","article-title":"Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity","volume":"50","author":"Mantovani","year":"2019","journal-title":"Immunity"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.1600-065X.2008.00701.x","article-title":"The interleukin-1 receptor\/Toll-like receptor superfamily: 10 years of progress","volume":"226","year":"2008","journal-title":"Immunol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1002\/pro.2441","article-title":"Structural biology of the IL-1 superfamily: Key cytokines in the regulation of immune and inflammatory responses","volume":"23","author":"Krumm","year":"2014","journal-title":"Protein Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.3389\/fimmu.2019.01412","article-title":"Structural basis of IL-1 family cytokine signaling","volume":"10","author":"Fields","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/nsmb.2260","article-title":"Structure of the activating IL-1 receptor signaling complex","volume":"19","author":"Thomas","year":"2012","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/S1359-6101(98)00018-5","article-title":"The interleukin 1 receptor: Ligand interactions and signal transduction","volume":"9","author":"Auron","year":"1998","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/386190a0","article-title":"Crystal structure of the type-I interleukin-1 receptor complexed with interleukin-1\u03b2","volume":"386","author":"Vigers","year":"1997","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"36927","DOI":"10.1074\/jbc.M006071200","article-title":"X-ray crystal structure of a small antagonist peptide bound to interleukin-1 receptor type 1","volume":"275","author":"Vigers","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1016\/j.immuni.2017.08.004","article-title":"IL-1 Family Cytokines Use Distinct Molecular Mechanisms to Signal through Their Shared Co-receptor","volume":"47","author":"Deredge","year":"2017","journal-title":"Immunity"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1016\/j.str.2019.05.011","article-title":"Functional Relevance of Interleukin-1 Receptor Inter-domain Flexibility for Cytokine Binding and Signaling","volume":"27","author":"Ge","year":"2019","journal-title":"Structure"},{"key":"ref_14","first-page":"1","article-title":"Identification of potential small molecule allosteric modulator sites on IL-1R1 ectodomain using accelerated conformational sampling method","volume":"10","author":"Yang","year":"2015","journal-title":"PLoS One"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7399","DOI":"10.1038\/s41598-020-64034-z","article-title":"Comparative Analyses of the Conformational Dynamics Between the Soluble and Membrane-Bound Cytokine Receptors","volume":"10","author":"Yang","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1107\/S0021889892009944","article-title":"PROCHECK: A program to check the stereochemical quality of protein structures","volume":"26","author":"Laskowski","year":"1993","journal-title":"J. Appl. Crystallogr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"W407","DOI":"10.1093\/nar\/gkm290","article-title":"ProSA-web: Interactive web service for the recognition of errors in three-dimensional structures of proteins","volume":"35","author":"Wiederstein","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1002\/bip.360221211","article-title":"Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features","volume":"22","author":"Kabsch","year":"1983","journal-title":"Biopolymers"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1007\/s00894-019-3964-0","article-title":"Physical properties of model biological lipid bilayers: Insights from all-atom molecular dynamics simulations","volume":"25","author":"Shahane","year":"2019","journal-title":"J. Mol. Model."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1016\/j.bbamem.2016.01.029","article-title":"Validating lipid force fields against experimental data: Progress, challenges and perspectives","volume":"1858","author":"Poger","year":"2016","journal-title":"Biochim. Biophys. Acta - Biomembr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1039\/C2CP42738A","article-title":"Cholesterol and POPC segmental order parameters in lipid membranes: Solid state 1 H\u2013 13 C NMR and MD simulation studies","volume":"15","author":"Ferreira","year":"2013","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1021\/ct900487a","article-title":"On the Validation of Molecular Dynamics Simulations of Saturated and cis -Monounsaturated Phosphatidylcholine Lipid Bilayers: A Comparison with Experiment","volume":"6","author":"Poger","year":"2010","journal-title":"J. Chem. Theory Comput."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5683","DOI":"10.1021\/acs.jctc.7b00643","article-title":"On the Calculation of Acyl Chain Order Parameters from Lipid Simulations","volume":"13","author":"Piggot","year":"2017","journal-title":"J. Chem. Theory Comput."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_25","unstructured":"(2021, December 23). RStudio Team RStudio: Integrated Development for R. Available online: https:\/\/www.rstudio.com."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1093\/bioinformatics\/bty968","article-title":"BlendMol: Advanced macromolecular visualization in Blender","volume":"35","author":"Durrant","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kent, B.R. (2015). 3D Scientific Visualization with Blender, Morgan & Claypool Publishers.","DOI":"10.1088\/978-1-6270-5612-0"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3913","DOI":"10.1073\/pnas.1217996110","article-title":"Design of a superior cytokine antagonist for topical ophthalmic use","volume":"110","author":"Hou","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1006\/jmbi.1993.1626","article-title":"Comparative Protein Modelling by Satisfaction of Spatial Restraints","volume":"234","author":"Blundell","year":"1993","journal-title":"J. Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1110\/ps.062416606","article-title":"Statistical potential for assessment and prediction of protein structures","volume":"15","author":"Shen","year":"2006","journal-title":"Protein Sci."},{"key":"ref_32","unstructured":"Sali, A. (2021, July 03). Make alpha helix - Modeller Wiki. Available online: https:\/\/salilab.org\/modeller\/wiki\/Makealphahelix."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"31664","DOI":"10.1074\/jbc.M403434200","article-title":"Crystal Structure of the Toll\/Interleukin-1 Receptor Domain of Human IL-1RAPL","volume":"279","author":"Khan","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic local alignment search tool","volume":"215","author":"Altschul","year":"1990","journal-title":"J. Mol. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s00251-020-01157-7","article-title":"A survey of TIR domain sequence and structure divergence","volume":"72","author":"Toshchakov","year":"2020","journal-title":"Immunogenetics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_37","unstructured":"Abraham, M., van der Spoel, D., Lindahl, E., Hess, B., and GROMACS Development Team (2021, September 23). GROMACS User Manual version 2019.3. Available online: http:\/\/www.gromacs.org."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera? A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1002\/jcc.21507","article-title":"g_membed: Efficient insertion of a membrane protein into an equilibrated lipid bilayer with minimal perturbation","volume":"31","author":"Wolf","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1002\/prot.22711","article-title":"Improved side-chain torsion potentials for the Amber ff99SB protein force field","volume":"78","author":"Piana","year":"2010","journal-title":"Proteins Struct. Funct. Bioinforma."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1016\/S0006-3495(97)78845-3","article-title":"Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature","volume":"72","author":"Berger","year":"1997","journal-title":"Biophys. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H","article-title":"LINCS: A linear constraint solver for molecular simulations","volume":"18","author":"Hess","year":"1997","journal-title":"J. Comput. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1063\/1.470117","article-title":"A smooth particle mesh Ewald method","volume":"103","author":"Essmann","year":"1995","journal-title":"J. Chem. Phys."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"014101","DOI":"10.1063\/1.2408420","article-title":"Canonical sampling through velocity rescaling","volume":"126","author":"Bussi","year":"2007","journal-title":"J. Chem. Phys."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7182","DOI":"10.1063\/1.328693","article-title":"Polymorphic transitions in single crystals: A new molecular dynamics method","volume":"52","author":"Parrinello","year":"1981","journal-title":"J. Appl. Phys."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"134101","DOI":"10.1063\/1.2013227","article-title":"A configurational temperature Nos\u00e9-Hoover thermostat","volume":"123","author":"Braga","year":"2005","journal-title":"J. Chem. Phys."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular dynamics with coupling to an external bath","volume":"81","author":"Berendsen","year":"1984","journal-title":"J. Chem. Phys."},{"key":"ref_49","unstructured":"(2020). Schr\u00f6dinger LLC The PyMOL Molecular Graphics System, Version 2.4.1, Schr\u00f6dinger LLC."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/386194a0","article-title":"A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist","volume":"386","author":"Schreuder","year":"1997","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s10852-005-9022-1","article-title":"Clustering Rules: A Comparison of Partitioning and Hierarchical Clustering Algorithms","volume":"5","author":"Reynolds","year":"2006","journal-title":"J. Math. Model. Algorithms"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Kaufman, L., and Rousseeuw, P.J. (1990). Finding Groups in Data, John Wiley & Sons, Inc.","DOI":"10.1002\/9780470316801"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2599\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:28:19Z","timestamp":1760135299000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2599"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,26]]},"references-count":52,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ijms23052599"],"URL":"https:\/\/doi.org\/10.3390\/ijms23052599","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,26]]}}}