Computational modeling study of IL-15-NGR peptide fusion protein: a targeted therapeutics for hepatocellular
Tehreem Fatima1, Mian Muhammad Mubasher2, Hafiz Muhammad Rehman3,4
1Centre for Applied Molecular Biology (CAMB), University of the Punjab, 87-West canal, Bank Road, Lahore, 53700, Pakistan.
Abstract:
The primary challenge to improving existing cancer treatment is to develop drugs that specifically target tumor cell. NGR peptide is tumor homing peptide that selectively target cancer cells while interleukin 15 is a pleiotropic cytokine with anticancer properties. This study computationally engineered a IL15-NGR fusion peptide by linking the homing peptide NGR with the targeting peptide IL-15. After evaluating and validating the chimeric peptide, we docked it to the IL-15Rα/IL-15Rβ/γc heterodimer receptor, examining the interactions and binding energy and lastly, molecular dynamics simulations were performed. The secondary and tertiary structures, along with physicochemical properties of the designed IL-15-NGR chimeric protein, were predicted using GOR IV, trRosetta and ProtParam online servers respectively. The quality and 3D structure validation were confirmed via ProSA-web and SAVES 6.0 analysis which predicted an ERRAT score of 96.72%, with 97.6% of residues in the Ramachandran plot, validating its structure. Finally, Docking, MD simulations and interaction analysis were performed using ClusPro 2.0 and GROMACS and PDBsum, which exhibited significant hydrogen bonding and salt bridges, confirming the formation of a stable docked complex. These results were further corroborated by simulation analysis, which demonstrated a stable and dynamic behavior of the docked complex in a biological environment. The predicted high expression value of fusion protein was 0.844 in E.coli using SOLUPROT tool. These findings suggest efficient expression of the IL15-NGR fusion protein if its gene is inserted into E. coli and indicates its potential as a safe and effective anticancer treatment, paving the way for targeted therapeutic interventions.
Insights
Researchers engineered a novel fusion peptide, IL15-NGR, combining tumor-homing NGR peptide with anticancer interleukin 15. Computational analysis confirmed its stable structure and effective binding to the target receptor, suggesting potential for targeted cancer therapy.
Area of Science:
- Biotechnology
- Computational Biology
- Oncology
Background:
- Developing targeted cancer therapies remains a key challenge.
- Interleukin 15 (IL-15) exhibits anticancer properties, while NGR peptide targets tumor cells.
- Combining these offers a strategy for enhanced tumor-specific drug delivery.
Purpose of the Study:
- To computationally engineer and validate a novel IL15-NGR fusion peptide.
- To assess the binding affinity and stability of the fusion peptide to its target receptor.
- To predict the feasibility of expressing the fusion protein in E. coli for potential therapeutic applications.
Main Methods:
- Computational engineering of IL15-NGR fusion peptide.
- Structure prediction (secondary, tertiary, physicochemical properties) using GOR IV, trRosetta, ProtParam.
- Structure validation using ProSA-web and SAVES 6.0 (Ramachandran plot, ERRAT score).
- Molecular docking and dynamics simulations (ClusPro 2.0, GROMACS).
- E. coli expression prediction (SOLUPROT).
Main Results:
- Validated secondary and tertiary structures with high quality scores (ERRAT 96.72%, Ramachandran 97.6%).
- Confirmed stable complex formation through docking and molecular dynamics simulations, showing significant hydrogen bonding and salt bridges.
- Predicted high expression potential (0.844) of the IL15-NGR fusion protein in E. coli.
Conclusions:
- The computationally designed IL15-NGR fusion peptide possesses a validated, stable structure.
- The fusion peptide demonstrates effective binding and stable complex formation with its target receptor.
- The IL15-NGR fusion protein shows potential for efficient expression in E. coli, indicating promise as a targeted anticancer therapeutic.
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