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Cited by 4Protein Structure and DynamicsCytokine Signaling Pathways and InteractionsReceptor Mechanisms and Signaling

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Rational design of monomeric IL37 variants guided by stability and dynamical analyses of IL37 dimers

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Sardag, Inci, Duvenci, Zeynep Sevval, Belkaya, Serkan, Timucin, Emel·2024·Computational and Structural Biotechnology Journal
DOI 10.1016/j.csbj.2024.04.037PMC PMC11177541

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Abstract

IL37 plays important roles in the regulation of innate immunity and its oligomeric status is critical to these roles. In its monomeric state, IL37 can effectively inhibit the inflammatory response of IL18 by binding to IL18R α , a capacity lost in its dimeric form, underlining the pivotal role of the oligomeric status of IL37 in its anti-inflammatory action. Until now, two IL37 dimer structures have been deposited in PDB, reflecting a substantial difference in their dimer interfaces. Given this discrepancy, we analyzed the PDB structures of the IL37 dimer (PDB IDs: 6ncu , 5hn1 ) along with a AF2-multimer prediction by molecular dynamics (MD) simulations. Results showed that the 5hn1 and AF2-predicted dimers have the same interface and stably maintained their conformations throughout simulations, while the recent IL37 dimer (PDB ID: 6ncu ) with a different interface did not, proposing a possible issue with the recent IL37 dimer structure ( 6ncu ). Next, focusing on the stable dimer structures, we have identified five critical positions of V71/Y85/I86/E89/S114, three new positions compared to the literature, that would reduce dimer stability without affecting the monomer structure. Two quintuple mutants were tested by MD simulations and showed partial or complete dissociation of the dimer. Overall, the insights gained from this study reinforce the validity of the 5hn1 and AF2 multimer structures, while also advancing our understanding of the IL37 dimer interface through the generation of monomer-locked IL37 variants.

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Graphical abstract CC BY · PubMed Central
Fig. 1 Binding interface of two crystal dimers 5hn1 and 6ncu from PDB. (a) Hydrophobic interface of the 5hn1 dimer composed of V71, Y85 and I86 from both subunits, which is sectioned by two symmetrical intermolecular interactions between K83 and D73, is visualized. (b) The interaction surface of the 6ncu is depicted showing the amino acids that are closely found at the interface. (c) Best superimposition of two biological assemblies were shown based on Cα RMSD.
Fig. 1 Binding interface of two crystal dimers 5hn1 and 6ncu from PDB. (a) Hydrophobic interface of the 5hn1 dimer composed of V71, Y85 and I86 from both subunits, which is sectioned by two symmetrical intermolecular interactions between K83 and D73, is visualized. (b) The interaction surface of the 6ncu is depicted showing the amino acids that are closely found at the interface. (c) Best superimposition of two biological assemblies were shown based on Cα RMSD.CC BY · PubMed Central
Fig. 2 Solvent accessible surface area (SASA) changes were calculated for all three dimers. First column shows the dimer SASA, the second and third columns show monomer SASA values, and the last column shows the interface SASA calculated by subtracting the dimer SASA from the sum of subunit SASA values.
Fig. 2 Solvent accessible surface area (SASA) changes were calculated for all three dimers. First column shows the dimer SASA, the second and third columns show monomer SASA values, and the last column shows the interface SASA calculated by subtracting the dimer SASA from the sum of subunit SASA values.CC BY · PubMed Central
Fig. 3 The relative displacement of one monomer (chain B) with respect to the other (chain A) for the first simulations of the (a) 5hn1, (b) 6ncu and (c) AF2 dimers. For each visual, center of mass of the monomers were shown by spheres colored according to simulation time (red: start, blue: end). (d) Panel shows the rest of replicate simulations of the 6ncu, wherein the dimer subunits are almost completely dissociated.
Fig. 3 The relative displacement of one monomer (chain B) with respect to the other (chain A) for the first simulations of the (a) 5hn1, (b) 6ncu and (c) AF2 dimers. For each visual, center of mass of the monomers were shown by spheres colored according to simulation time (red: start, blue: end). (d) Panel shows the rest of replicate simulations of the 6ncu, wherein the dimer subunits are almost completely dissociated.CC BY · PubMed Central
Fig. 4 Superimposed dimer interface (80-87) of 5hn1 (mauve) and 6ncu (cyan) structures were shown. SASA and radius of gyration (RG) of this interface were measured throughout simulations for both chains. 6ncu chains were colored by green, 5hn1 chains were colored by orange and AF2 chains were colored by purple. Top row contains two representative snapshots from the 6ncu simulations showing a notable change in the SASA and RG of the epitope during simulations.
Fig. 4 Superimposed dimer interface (80-87) of 5hn1 (mauve) and 6ncu (cyan) structures were shown. SASA and radius of gyration (RG) of this interface were measured throughout simulations for both chains. 6ncu chains were colored by green, 5hn1 chains were colored by orange and AF2 chains were colored by purple. Top row contains two representative snapshots from the 6ncu simulations showing a notable change in the SASA and RG of the epitope during simulations.CC BY · PubMed Central
Fig. 5 The locations of selected human IL37 variants, I177T, R152W, V113F and S114F and other residues within range 5 Å. (a) The positions I177 and R152 and (b) V113 and S114 along with surrounding amino acids were shown in surface representations. Relative accessible surface area for the dimer and monomer structures were also given for all amino acids. The impact of the observed human variants of these positions on the dimer and monomer stability were given in kcal.mol−1.
Fig. 5 The locations of selected human IL37 variants, I177T, R152W, V113F and S114F and other residues within range 5 Å. (a) The positions I177 and R152 and (b) V113 and S114 along with surrounding amino acids were shown in surface representations. Relative accessible surface area for the dimer and monomer structures were also given for all amino acids. The impact of the observed human variants of these positions on the dimer and monomer stability were given in kcal.mol−1.CC BY · PubMed Central
Fig. 6 Initial dimer conformation was illustrated at the top. Snapshots that were taken after 29.0 and 50.8 ns from Y85C and Y85K containing mutant simulations, respectively were shown at the bottom. Red arrows indicate the relative movement of one of the monomers with respect to its initial position in the dimer conformation shown at the top.
Fig. 6 Initial dimer conformation was illustrated at the top. Snapshots that were taken after 29.0 and 50.8 ns from Y85C and Y85K containing mutant simulations, respectively were shown at the bottom. Red arrows indicate the relative movement of one of the monomers with respect to its initial position in the dimer conformation shown at the top.CC BY · PubMed Central

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Citations

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Research works printed but not linked: 66

  1. 10.1111/imr.12621 · DOI · Paper page
  2. van de VeerdonkFrank L.StoeckmanAngela K.WuGoupingBoeckermannAaron N.AzamTaniaNeteaMihai G.Il-38 binds to the il-36 receptor and has biological effects on immune cells similar to il-36 receptor antagonistProc Natl Acad Sci109820123001300522315422 · DOI
  3. RudloffInaGodsellJackNold-PetryClaudia A.HarrisJamesHoiAlbertaMorandEric F.Brief report: interleukin-38 exerts antiinflammatory functions and is associated with disease activity in systemic lupus erythematosusArthritis Rheumatol671220153219322526314375 · DOI
  4. DinarelloCharlesArendWilliamSimsJohnSmithDirkBlumbergHalO'NeillLukeIl-1 family nomenclatureNat Immunol1111201097320959797 · DOI
  5. 10.1073/pnas.1819672116 · DOI
  6. Ellisdon Andrew M. Nold-Petry Claudia A. D'Andrea Laura Cho Steven X. Lao Jason C. Rudloff Ina Homodimerization attenuates the anti-inflammatory activity of interleukin-37 Sci Immunol 2 8 2017 eaaj1548
  7. Zeng Huiqiong Zhou Kaixia Ye Zhizhong Biology of interleukin-37 and its role in autoimmune diseases Exp Ther Med 24 2 2022 1 10
  8. 10.1016/j.chembiol.2021.10.004 · DOI
  9. Sánchez-FernándezAlbaZandeeStephanieAmo-AparicioJesúsCharabatiMarcPratAlexandreGarlandaCeciliaIl-37 exerts therapeutic effects in experimental autoimmune encephalomyelitis through the receptor complex il-1r5/il-1r8Theranostics1112021133391457 · DOI
  10. 10.1007/s13238-017-0408-4 · DOI
  11. 10.1021/acs.jcim.2c00054 · DOI
  12. 10.1093/bioinformatics/btn268 · DOI
  13. 10.1126/science.2471267 · DOI
  14. 10.1534/genetics.117.300064 · DOI
  15. 10.1016/j.csbj.2023.06.021 · DOI
  16. ŠaliAndrejBlundellTom L.Comparative protein modelling by satisfaction of spatial restraintsJ Mol Biol234319937798158254673 · DOI · Paper page
  17. 10.1110/ps.062416606 · DOI
  18. 10.1126/science.abj8754 · DOI · Paper page
  19. Evans Richard O'Neill Michael Pritzel Alexander Antropova Natasha Senior Andrew Green Tim Protein complex prediction with alphafold-multimer bioRxiv 2021 2021-10
  20. 10.1038/s41592-022-01488-1 · DOI · Paper page
  21. MirditaMilotSteineggerMartinSödingJohannesMmseqs2 desktop and local web server app for fast, interactive sequence searchesBioinformatics351620192856285830615063 · DOI · Paper page
  22. 10.1038/nbt.3988 · DOI · Paper page
  23. Yang Zhenyu Zeng Xiaoxi Zhao Yi Chen Runsheng Alphafold2 and its applications in the fields of biology and medicine Signal Transduct Targeted Ther 8 1 2023 115 · DOI
  24. 10.1002/jcc.20945 · DOI · Paper page
  25. 10.1002/jcc.21287 · DOI
  26. Lee Jumin Cheng Xi Swails Jason M. Yeom Min Sun Eastman Peter K. Lemkul Justin A. Charmm-gui input generator for namd, gromacs, amber, openmm, and charmm/openmm simulations using the charmm36 additive force field Biophys J 110 3 2016 641a
  27. DolinskyTodd J.NielsenJens E.McCammonJ. AndrewBakerNathan A.Pdb2pqr: an automated pipeline for the setup of Poisson–Boltzmann electrostatics calculationsNucleic Acids Res32suppl_22004W665W66715215472 · DOI
  28. 10.1002/pro.3280 · DOI
  29. 10.1002/jcc.20289 · DOI · Paper page
  30. MacKerell A.D. Jr. Bashford D. Bellott M. Dunbrack R.L. Jr. Evanseck J.D. Field M.J. All-atom empirical potential for molecular modeling and dynamics studies of proteins J Phys Chem B 102 18 1998 3568 3616 · DOI
  31. HuangJingMacKerellAlexander D.Jr.Charmm36 all-atom additive protein force field: validation based on comparison to nmr dataJ Comput Chem342520132135214523832629 · DOI
  32. 10.1063/1.445869 · DOI
  33. 10.1063/1.464397 · DOI
  34. Martyna Glenn J. Tobias Douglas J. Klein Michael L. Constant pressure molecular dynamics algorithms J Chem Phys 101 5 1994 4177 4189 · DOI
  35. Feller Scott E. Zhang Yuhong Pastor Richard W. Brooks Bernard R. Constant pressure molecular dynamics simulation: the Langevin piston method J Chem Phys 103 11 1995 4613 4621 · DOI
  36. Pastor Richard W. Brooks Bernard R. Szabo Attila An analysis of the accuracy of Langevin and molecular dynamics algorithms Mol Phys 65 6 1988 1409 1419 · DOI
  37. Gowers Richard J. Linke Max Barnoud Jonathan Reddy Tyler JE Melo Manuel N. Seyler Sean L. Mdanalysis: a python package for the rapid analysis of molecular dynamics simulations Proceedings of the 15th python in science conference vol. 98 2016 SciPy Austin TX 105 · DOI
  38. Michaud-AgrawalNaveenDenningElizabeth J.WoolfThomas B.BecksteinOliverMdanalysis: a toolkit for the analysis of molecular dynamics simulationsJ Comput Chem321020112319232721500218 · DOI
  39. HumphreyWilliamDalkeAndrewSchultenKlausVmd: visual molecular dynamicsJ Mol Graph141199633388744570 · DOI · Paper page
  40. 10.1002/pro.3943 · DOI
  41. 10.1002/pro.3235 · DOI · Paper page
  42. Meng Elaine C. Goddard Thomas D. Pettersen Eric F. Couch Greg S. Pearson Zach J. Morris John H. Ucsf chimerax: tools for structure building and analysis Protein Sci 2023 e4792
  43. GrantBarry J.SkjaervenLarsYaoXin-QiuThe bio3d packages for structural bioinformaticsProtein Sci3012021203032734663 · DOI
  44. SchymkowitzJoostBorgJesperStricherFrancoisNysRobbyRousseauFredericSerranoLuisThe foldx web server: an online force fieldNucleic Acids Res33suppl_22005W382W38815980494 · DOI · Paper page
  45. BillR.MillerI.I.I.Dwight McGeeT.Jr.SwailsJason M.HomeyerNadineGohlkeHolgerMmpbsa. py: an efficient program for end-state free energy calculationsJ Chem Theory Comput8920123314332126605738 · DOI
  46. CaseDavid A.AktulgaHasan MetinBelfonKellonCeruttiDavid S.Andrés CisnerosG.WilianViníciusAmbertoolsJ Chem Inf Model632020236183619137805934 · DOI
  47. 10.1016/j.csbj.2021.09.003 · DOI
  48. OliveiraNuno F.B.RodriguesFilipe E.P.VitorinoJoão N.M.FaíscaPatrícia F.N.MachuqueiroMiguelInterfacial dynamics and growth modes of β2-microglobulin dimersJ Chem Inf Model631420234447445737132512 · DOI
  49. Zhang Zinan Z. Zhang Yu He Tingyan Sweeney Colin L. Baris Safa Karakoc-Aydiner Elif Homozygous il37 mutation associated with infantile inflammatory bowel disease Proc Natl Acad Sci 118 10 2021 e2009217118
  50. Chen Yuting Lu Haoyu Zhang Ning Zhu Zefeng Wang Shuqin Li Minghui Premps: predicting the effects of single mutations on protein stability bioRxiv 2020 2020-04
  51. Dang Dung Thanh Molecular approaches to protein dimerization: opportunities for supramolecular chemistry Front Chem 10 2022 829312
  52. 10.1016/j.tibs.2004.09.006 · DOI
  53. PlaxcoKevin W.GrossMichaelProtein complexes: the evolution of symmetryCurr Biol1912009R25R2619138586 · DOI
  54. KrissinelEvgenyHenrickKimInference of macromolecular assemblies from crystalline stateJ Mol Biol3723200777479717681537 · DOI
  55. 10.1073/pnas.1810054115 · DOI
  56. 10.1111/febs.15717 · DOI
  57. DahanayakeJayangika N.GautamDevaki N.VermaRajniMitchell-KochKatie R.To keep or not to keep? The question of crystallographic waters for enzyme simulations in organic solventMol Simul421220161001101327403032 · DOI
  58. 10.1111/j.1742-4658.2007.06178.x · DOI
  59. 10.1110/ps.073360508 · DOI
  60. XuQifangDunbrackRoland L.The protein common interface database (protcid)—a comprehensive database of interactions of homologous proteins in multiple crystal formsNucleic Acids Res39suppl_12010D761D77021036862
  61. BaskaranKumaranDuarteJose M.BiyaniNikhilBlivenSpencerCapitaniGuidoA pdb-wide, evolution-based assessment of protein-protein interfacesBMC Struct Biol141201411124410837
  62. 10.1107/S2052252514005442 · DOI
  63. LevyEmmanuel D.Piqsi: protein quaternary structure investigationStructure151120071364136717997962 · DOI
  64. LiWenyuSrinivasulaSrinivasa M.ChaiJijieLiPingweiWuJia-WeiZhangZhiJiaStructural insights into the pro-apoptotic function of mitochondrial serine protease htra2/omiNat Struct Biol96200243644111967569 · DOI
  65. Timucin Emel Ugur Sezerman O. The conserved lid tryptophan, w211, potentiates thermostability and thermoactivity in bacterial thermoalkalophilic lipases PLoS ONE 8 12 2013 e85186
  66. GenhedenSamuelRydeUlfThe mm/pbsa and mm/gbsa methods to estimate ligand-binding affinitiesExpert Opin Drug Discov105201544946125835573 · DOI

Metadata

Authors
Sardag, I., Duvenci, Z. S., Belkaya, S., & Timucin, E.
Affiliations
  • Boğaziçi University (TR)
  • Acibadem Mehmet Ali Aydinlar University, Institute of Health Sciences, Department of Biostatistics and Bioinformatics, Istanbul 34752, Turkey
  • Bilkent University (TR)
Corresponding author
Belkaya, Serkan
ORCID
Venue
Computational and Structural Biotechnology Journal
Publisher
American Association for the Advancement of Science (AAAS)
Published
2024-04-22
Volume
23
Pages
1854-1863
ISSN
2001-0370 (ISSN-L)
DOI
10.1016/j.csbj.2024.04.037
PMC
PMC11177541
OpenAlex
W4394996705
Cited by
4
References
5
Citations by year
2026: 1 · 2025: 3
FWCI
0.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Computational and Structural Biotechnology Journal (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Bilkent University Institutional Repository (Bilkent University) (submittedVersion, cc-by)
Funders
  • Türkiye Bilimsel ve Teknolojik Araştırma Kurumu
  • EMBO (IG 4727)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
IL-37, dimer stability, dimer interface, oligomeric state, molecular dynamics simulation, dimer dissociation, critical residues

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