{
  "abstract": "The interaction between Interleukin-17A (IL-17A) and its receptor IL-17RA plays a key role in pro-inflammatory signal transduction and is implicated in the pathogenesis of inflammatory autoimmune diseases. Blocking this protein-protein interaction is a major approach to developing therapeutic agents to inhibit IL-17A-induced signaling. Predicting the consequences of mutations on structure and function in proteins can be accomplished by using computational methods, which are relatively inexpensive and rapid compared with experimental methods. Here, we used a multidimensional in silico approach to gain insight into the functional and thermodynamic consequences of targeted mutation of hotspot residues of IL-17A. The focus of our analysis was on the residues in the two chains that are equivalent to hotspot residues of the related cytokine, IL-17F, at positions 55 and 67 of chain B and 85 and 86 of chain A. Comprehensive analysis of the conformational dynamics, interaction profiles, and structural transitions of the four mutant variant systems (R55V, W67V, Y85I, and H86S) and the wild-type system was performed based on molecular dynamics (MD) simulations and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations. A total of 3 μs simulations were performed: three 200 ns replicates for each of the wild-type and mutant complexes. Results from principal component analysis (PCA) and free energy landscape (FEL) analyses indicate conformational destabilization of the mutant systems. These findings help to elucidate the mechanisms of molecular interactions involved in the dynamics of cytokine–receptor interaction. Changes in these important PSN network parameters resulted in differences in hub connectivity and distribution of the links between the systems, which suggests allosteric perturbations and remodeling of the system in the interaction between IL-17A and IL-17RA when compared to the wild-type systems. The multiple-replica MD simulation protocol provided insight into how mutations affected the structure, contact networks, dynamics, and binding affinity of the IL-17A/IL-17RA complex, shedding light on the IL-17A downstream signaling cascades. Overall, this study provides a fundamental framework for designing therapeutic strategies to regulate IL-17A-mediated inflammatory diseases.",
  "abstract_shown": true,
  "affiliations": [
    "H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological, Sciences, University of Karachi, Karachi, Pakistan",
    "Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan",
    "Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia",
    "Kentucky College of Osteopathic Medicine, University of Pikeville, Pikeville, Kentucky, United States of America"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Afsheen Razzaq"
    },
    {
      "affs": [
        1
      ],
      "name": "Madiha Sardar"
    },
    {
      "affs": [
        2
      ],
      "name": "Mamona Mushtaq"
    },
    {
      "affs": [
        3
      ],
      "name": "Mohammad Nur-e-Alam"
    },
    {
      "name": "Muhammad Nabeel Ghayur"
    },
    {
      "name": "Zaheer Ul-Haq"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bd60x5f3qzjkh.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pone.0361876",
  "fulltext_url": null,
  "id": "bd60x5f3qzjkh",
  "issns": [
    "1932-6203"
  ],
  "landing_url": "https://doi.org/10.1371/journal.pone.0361876",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Protein Structure and Dynamics"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Biochemical simulations"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteomics/Protein interaction networks"
    ],
    [
      "plos",
      "/Biology and life sciences/Computational biology/Biochemical simulations"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Mutation/Point mutation"
    ],
    [
      "plos",
      "/Computer and information sciences/Network analysis/Protein interaction networks"
    ],
    [
      "plos",
      "/Medicine and health sciences/Pharmacology/Drug interactions"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Computational chemistry/Molecular dynamics"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Physical chemistry/Chemical bonding/Hydrogen bonding"
    ],
    [
      "plos",
      "/Physical sciences/Mathematics/Statistics/Statistical methods/Multivariate analysis/Principal component analysis"
    ],
    [
      "plos",
      "/Physical sciences/Physics/Thermodynamics/Free energy"
    ],
    [
      "plos",
      "/Research and analysis methods/Mathematical and statistical techniques/Statistical methods/Multivariate analysis/Principal component analysis"
    ]
  ],
  "openalex": "W7225430682",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-06",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/bd60x5f3qzjkh.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T12:20:24Z",
      "native_id": "10.1371/journal.pone.0361876",
      "source": "plos",
      "url": "https://doi.org/10.1371/journal.pone.0361876"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "plos:proteomics",
      "subfield": "proteomics-metabolomics"
    },
    {
      "field": "biology",
      "origin": "plos:computational biology",
      "subfield": "bioinformatics"
    },
    {
      "field": "mathematics",
      "origin": "plos:statistical methods",
      "subfield": "statistics"
    }
  ],
  "title": "Mutation-induced structural and dynamic perturbations at the IL-17A–IL-17RA interface: Therapeutic insights from multi-replicate molecular dynamics simulations",
  "title_text": "Mutation-induced structural and dynamic perturbations at the IL-17A–IL-17RA interface: Therapeutic insights from multi-replicate molecular dynamics simulations",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T12:20:48Z",
  "url": "https://research.draconitic.com/paper/bd60x5f3qzjkh",
  "venue": "PLOS One",
  "versions": []
}