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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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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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CoChat. (2026). Citation check: Rational design of monomeric IL37 variants guided by stability and dynamical analyses of IL37 dimers. https://app.cochat.ai/papers/10.1016/j.csbj.2024.04.037
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Sardag, I., Duvenci, Z. S., Belkaya, S., & Timucin, E. (2024). Rational design of monomeric IL37 variants guided by stability and dynamical analyses of IL37 dimers. Computational and Structural Biotechnology Journal. https://doi.org/10.1016/j.csbj.2024.04.037