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Computational Deciphering of the Role of S100A8 and S100A9 Proteins and Their Changes in the Structure Assembly Influences Their Interaction with TLR4, RAGE, and CD36

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Abstract

S100A8 and S100A9 belong to the calcium-binding, damage associated molecular pattern (DAMP) proteins shown to aggravate the pathogenesis of rheumatoid arthritis (RA) through their interaction with the TLR4, RAGE and CD36 receptors. S100A8 and S100A9 proteins tend to exist in monomeric, homo and heterodimeric forms, which have been implicated in the pathogenesis of RA, via interacting with Pattern Recognition receptors (PRRs). The study aims to assess the influence of changes in the structure and biological assembly of S100A8 and S100A9 proteins as well as their interaction with significant receptors in RA through computational methods and surface plasmon resonance (SPR) analysis. Molecular docking analysis revealed that the S100A9 homodimer and S100A8/A9 heterodimer showed higher binding affinity towards the target receptors. Most S100 proteins showed good binding affinity towards TLR4 compared to other receptors. Based on the 50 ns MD simulations, TLR4, RAGE, and CD36 formed stable complexes with the monomeric and dimeric forms of S100A8 and S100A9 proteins. However, SPR analysis showed that the S100A8/A9 heterodimers formed stable complexes and exhibited high binding affinity towards the receptors. SPR data also indicated that TLR4 and its interactions with S100A8/A9 proteins may play a primary role in the pathogenesis of RA, with additional contributions from CD36 and RAGE interactions. Subsequent in vitro and in vivo investigations are warranted to corroborate the involvement of S100A8/A9 and the expression of TLR4, RAGE, and CD36 in the pathophysiology of RA.

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Acknowledgements

The authors would like to acknowledge SPR Facility, National Centre for Cell Science (NCCS), Pune, for the facility and assistance provided throughout the study.

Funding

This work was supported by the Indian Council of Medical Research (ICMR), New Delhi (Sanction order No: F. No. 58/12/2020/PHA/BMS Dtd: 04/03/2022).

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  1. Department of Pharmaceutical Technology, Bharathidasan Institute of Technology Campus, University College of Engineering, Anna University, Tiruchirappalli, Tamil Nadu, 620 024, India

    Sivasakthi Paramasivam, Senthamil Selvan Perumal & Sanmuga Priya Ekambaram

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Methodology, formal analysis, Data collection, interpretation, writing - S.P.; conceptualization, critical revision of the manuscript – S.S.P.; Conceptualization, critical revision of the manuscript, supervision of the study, funding acquisition – S.P.E. All authors reviewed the manuscript.

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Correspondence to Sanmuga Priya Ekambaram.

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Paramasivam, S., Perumal, S.S. & Ekambaram, S.P. Computational Deciphering of the Role of S100A8 and S100A9 Proteins and Their Changes in the Structure Assembly Influences Their Interaction with TLR4, RAGE, and CD36. Protein J (2024). https://doi.org/10.1007/s10930-024-10186-0

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