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Design of inhibitor peptide sequences based on the interfacial knowledge of the protein G-IgG crystallographic complex and their binding studies with IgG

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Abstract

Protein–protein interactions (PPI) have emerged as valuable targets in medicinal chemistry due to their key roles in important biological processes. The modulation of PPI by small peptides offers an excellent opportunity to develop drugs against human diseases. Here, we exploited the knowledge of the binding interface of the IgG-protein G complex (PDB:1FCC) for designing peptides that can inhibit these complexes. Herein, we have designed several closely related peptides, and the comparison of results from experiments and computational studies indicated that all the peptides bind close to the expected binding site on IgG and the complexes are stable. A minimal sequence consisting of 11 amino acids (P5) with binding constants in the range of 100 nM was identified. We propose that the main affinity differences across the series of peptides arose from the presence of polar amino acid residues. Further, the molecular dynamic studies helped to understand the dynamic properties of complexes in terms of flexibility of residues and structural stability at the interface. The ability of P5 to compete with the protein G in recognizing IgG can help in the detection and purification of antibodies. Further, it can serve as a versatile tool for a better understanding of protein–protein interactions.

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Data availability

The data that support the findings of this study are available on request from the corresponding author.

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Acknowledgements

This work was supported by grants from DST SERB (ECR/2016/000942), UPEII JNU, and DST Purse. We also thank AIRF for instrument facility.

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Authors and Affiliations

  1. School of Physical Sciences, Jawaharlal Nehru University, New Delhi, 110067, India

    Neetu Tanwar, Soumya Aggarwal & Manoj Munde

  2. Department of Nephrology, Washington University School of Medicine, St. Louis, MO, USA

    Rupal Ojha

  3. Department of Biochemistry, University of Delhi South Campus, New Delhi, India

    Vijay Kumar Prajapati

Authors
  1. Neetu Tanwar
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  2. Rupal Ojha
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  3. Soumya Aggarwal
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  4. Vijay Kumar Prajapati
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  5. Manoj Munde
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Contributions

Neetu Tanwar and Soumya Aggarwal performed the experimental study. Manoj Munde conceived the idea and supervised the project. Rupal Ojha and Vijay Kumar Prajapati contributed to the computational study. All the authors analysed the data and contributed to the writing and editing of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Manoj Munde.

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Tanwar, N., Ojha, R., Aggarwal, S. et al. Design of inhibitor peptide sequences based on the interfacial knowledge of the protein G-IgG crystallographic complex and their binding studies with IgG. Eur Biophys J 53, 159–170 (2024). https://doi.org/10.1007/s00249-024-01704-0

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