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A High Throughput MHC II Binding Assay for Quantitative Analysis of Peptide Epitopes
Published on: March 25, 2014
The HER2 target for designing novel multi-peptide vaccine against breast cancer using immunoinformatics and molecular
Faezeh Firuzpour1,2, Maryam Barancheshmeh3, Fariba Fallah Ziarani4
1Student Research Committee, Babol University of Medical Sciences, Babol, Iran.
Background:
Breast cancer (BC) remains a global health emergency, particularly HER2-positive subtypes, which are aggressive and resistant to conventional therapies. Despite advancements, therapeutic resistance and limited immune memory underline the need for novel treatment approaches such as multi-epitope vaccines.
Objective:
This study investigates the design and effectiveness of a novel in silico multi-epitope vaccine that is capable of targeting HER2 in breast cancer using immunoinformatics, structural modeling, and immune simulation approaches.
Methods:
UniProt was used to retrieve the HER2 protein sequences. Cytotoxic Tlymphocyte (CTL) and helper T lymphocyte (HTL) epitopes were predicted using IEDB and CTLPred, and filtered for antigenicity, IFN-γ production, and population coverage. The vaccine construct was designed by linking selected epitopes to PADRE, TAT peptide, and adjuvants using appropriate linker sequences. An evaluation of physicochemical, allergenic, and toxicological properties was carried out on the 322-amino-acid vaccine construct. Secondary and tertiary structures were predicted using PSIPRED and Robetta, refined with GalaxyRefine, and validated through Ramachandran plots, ERRAT, and ProSA-web. Molecular docking with TLR4 was conducted using HDOCK. Molecular dynamics simulations (MD) were performed with GROMACS for 100 ns and analyzed using RMSD, RMSF, PCA, DCCM, and MM-PBSA. Immune simulations were performed using C-ImmSim.
Results:
The final vaccine construct was found to be non-allergenic, antigenic (VaxiJen score: 0.59) and stable (instability index: 23.18). Tertiary structure validation yielded a favorable Ramachandran distribution (83 %), an ERRAT score of 90.12, and a Z-score of -8.35. Docking showed strong binding to TLR4 (score:296.23, with 6 ion bridges and 7 hydrogen bonds). Stable conformation of the vaccine construct with low fluctuations and high interaction correlation was derived through MD simulations. MM-PBSA calculated a binding free energy of -112.71 kJ/mol. Immune simulations predicted robust humoral and cellular immune responses with increased IFN-γ, IL-2, CTLs, and memory B-cells.
Conclusion:
The proposed HER2-targeted multi-epitope vaccine confirmed promising immunogenicity, structural stability, and potential global population coverage. It represents a novel, rationally designed immunotherapy candidate against HER2-positive breast cancer. However, further in vitro and in vivo validations are required to confirm its clinical application.
Insights
A novel multi-epitope vaccine targeting HER2-positive breast cancer shows promise. Computational analysis indicates strong immunogenicity and structural stability, suggesting potential as a new immunotherapy. Further validation is needed for clinical use.
Area of Science:
- Immunoinformatics and computational biology
- Vaccine design and development
- Cancer immunotherapy
Background:
- HER2-positive breast cancer is aggressive and treatment-resistant.
- Existing therapies have limitations in efficacy and immune memory.
- Novel approaches like multi-epitope vaccines are needed.
Purpose of the Study:
- To design and evaluate an in silico multi-epitope vaccine targeting HER2 in breast cancer.
- To utilize immunoinformatics, structural modeling, and immune simulations for vaccine development.
- To assess the vaccine construct's immunogenicity, stability, and potential efficacy.
Main Methods:
- HER2 protein sequences retrieved from UniProt.
- T-cell epitopes predicted using IEDB and CTLPred, filtered for key parameters.
- Vaccine construct designed with linkers, adjuvants, and PADRE/TAT peptides.
- Physicochemical, allergenic, and toxicological properties evaluated.
- Structural modeling and validation performed using multiple computational tools.
- Molecular docking with TLR4 and molecular dynamics simulations conducted.
- Immune simulations performed using C-ImmSim.
Main Results:
- The vaccine construct is non-allergenic, antigenic (VaxiJen score: 0.59), and stable (instability index: 23.18).
- Structural validation confirmed favorable properties (Ramachandran plot, ERRAT, ProSA-web).
- Strong binding to TLR4 observed via molecular docking (score: 296.23).
- Molecular dynamics simulations indicated a stable conformation with significant binding energy (-112.71 kJ/mol).
- Immune simulations predicted robust cellular and humoral responses, including increased IFN-γ, IL-2, CTLs, and memory B-cells.
Conclusions:
- The in silico designed HER2-targeted multi-epitope vaccine demonstrates significant immunogenic potential and structural stability.
- This rationally designed vaccine represents a promising candidate for HER2-positive breast cancer immunotherapy.
- Further in vitro and in vivo studies are essential to validate its clinical applicability.
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