3-Layer-based analysis of peptide–MHC interaction: In silico
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- 作者：Bernhard Knapp ; Ulrich Omasits ; Barbara Bohle ; Bernard Maillere ; Christof Ebner ; Wolfgang Schreiner ; Beatrice Jahn-Schmid
- 关键词：Peptide/MHC binding ; Peptide/MHC class II– ; TCR interaction ; T cell epitope prediction ; Molecular Dynamics ; Simulation ; T cell activation ; Allergen ; Art v 1
- 刊名：Molecular Immunology
- 出版年：2009
- 出版时间：May 2009
- 年：2009
- 卷：46
- 期：8-9
- 页码：1839-1844
- 全文大小：721 K
文摘
CD4+ T cells recognize peptides bound to major histocompatibility complex (MHC) class II molecules on the surface of antigen presenting cells by their T cell receptor (TCR). Using a well-characterized allergen-specific model we studied peptide/MHC (pMHC) interactions by combining computational methods with experimental analyses. A 12-mer and an 18-mer peptide, both containing the human leukocyte antigen (HLA)-DR1-restricted, immunodominant T cell epitope of Art v 1, the major mugwort pollen allergen, were compared. A Molecular Dynamics simulation for a real time of 20 ns using GROMACS was performed. To this aim, the peptides were modelled into the binding groove of HLA-DRB1*0101 using different amino acid substitution tools. Binding of synthetic peptides to purified HLA-DRB1*0101 molecules was analysed in competition assays. The potency of the peptides to activate Art v 1-specific T cells was assessed using oligo- and monoclonal Art v 1-specific T cell cultures expanded from mugwort allergic individuals.
All approaches revealed that the 18-mer peptide possessed higher HLA DR affinity as compared to the 12-mer. Computer modelling indicated that a loop-like structure within the additional N-terminal peptide flanking region of the 18-mer contributed to the pMHC interaction. Our approach, to combine computational methods validated by experimental results, demonstrates that Molecular Dynamics simulation may be a useful tool for the prediction of pMHC interactions in the future with possible applications in T cell-based immunotherapy e.g. in Type I allergy.