A Comparative Approach Linking Molecular Dynamics of Altered Peptide Ligands and MHC with In Vivo Immune Responses

Knapp, Bernhard; Omasits, Ulrich; Schreiner, Wolfgang; Epstein, Michelle M.

doi:10.1371/journal.pone.0011653

Cited by 31 publications

(29 citation statements)

References 30 publications

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“…These structures most likely are important for T cell reactivity. We have previously reported effects of such protruding peptide segments on T cell activation for peptide flanking regions [34] and altered peptide ligands with high sequence similarity [35]. Thus, we suggest that the C-terminal Art v 1 25-36 -residues protruding from the peptide binding groove are relevant for interactions with TCR in vivo.…”

Section: Discussionmentioning

confidence: 83%

Association of HLA-DR1 with the allergic response to the major mugwort pollen allergen: molecular background

et al. 2012

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BackgroundMugwort pollen allergens represent the main cause of pollinosis in late summer. The major allergen, Art v 1, contains only one single immunodominant, solely HLA-DR-restricted T cell epitope (Art v 125-36). The frequency of HLA-DRB1*01 is highly increased in mugwort-allergic individuals and HLA-DR1 serves as restriction element for Art v 125-36. However, Art v 125-36 also binds to HLA-DR4 with high affinity and DR1-restricted Art v 125-36 -specific T cell receptors can be activated by HLA-DR4 molecules. To understand the predominance of HLA-DR1 in mugwort allergy in spite of the degeneracy in HLA/peptide-binding and TCR-recognition, we investigated the molecular background of Art v 125-36 /MHC/TCR interactions in the context of HLA-DR1 compared to -DR4.ResultsThe majority of Art v 125-36 -specific T cell lines and clones from HLA-DR1 carrying, mugwort pollen-allergic donors reacted to synthetic and naturally processed Art v 1–peptides when presented by HLA-DR1 or HLA-DR4 expressing antigen presenting cells. However, at limiting peptide concentrations DR1 was more effective in T cell stimulation. In addition, the minimal epitope for 50% of Art v 125-36 -specific T cells was shorter for DR1 than for DR4. In vitro binding assays of Art v 125-36 mutant peptides to isolated DR1- and DR4-molecules indicated similar binding capacities and use of the same register. In silico simulation of Art v 125-36 binding to HLA-DR1 and -DR4 suggested similar binding of the central part of the peptide to either molecule, but a higher flexibility of the N- and C-terminal amino acids and detachment at the C-terminus in HLA-DR1.ConclusionsThe predominance of HLA-DR1 in the response to Art v 125-36 may be explained by subtle conformation changes of the peptide bound to DR1 compared to DR4. Computer simulation supported our experimental data by demonstrating differences in peptide mobility within the HLA-DR complex that may influence TCR-binding. We suggest that the minor differences observed in vitro may be more relevant in the microenvironment in vivo, so that only presentation by HLA-DR1, but not -DR4 permits successful T cell activation.

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Section: Discussionmentioning

confidence: 83%

Association of HLA-DR1 with the allergic response to the major mugwort pollen allergen: molecular background

et al. 2012

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“…The three-stage connection between peptide-MHC dynamical features, T cell affinity and activation potency is quite complex [7], [8] but, importantly, the most accepted TCR binding models [9], [10], [11], [12], [13] are based on a reciprocal conformational plasticity of both TCR and peptide-MHC, thus requiring a certain degree of peptide-MHC flexibility for a successful TCR recognition and then a conformational adjustment upon TCR binding [14], [15]. Recently the issue was investigated by many groups, in particular some authors [16], [17] provided important evidences, both computational and experimental, supporting a direct link between MHC protein flexibility – ‘floppy state’ – and enhanced peptide loading capabilities, with or without the help of an ancillary peptide loading enhancer protein called DM.…”

Section: Introductionmentioning

confidence: 99%

Structural and Dynamical Insights on HLA-DR2 Complexes That Confer Susceptibility to Multiple Sclerosis in Sardinia: A Molecular Dynamics Simulation Study

et al. 2013

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Sardinia is a major Island in the Mediterranean with a high incidence of multiple sclerosis, a chronic autoimmune inflammatory disease of the central nervous system. Disease susceptibility in Sardinian population has been associated with five alleles of major histocompatibility complex (MHC) class II DRB1 gene. We performed 120 ns of molecular dynamics simulation on one predisposing and one protective alleles, unbound and in complex with the two relevant peptides: Myelin Basic Protein and Epstein Barr Virus derived peptide. In particular we focused on the MHC peptide binding groove dynamics. The predisposing allele was found to form a stable complex with both the peptides, while the protective allele displayed stability only when bound with myelin peptide. The local flexibility of the MHC was probed dividing the binding groove into four compartments covering the well known peptide anchoring pockets. The predisposing allele in the first half cleft exhibits a narrower and more rigid groove conformation in the presence of myelin peptide. The protective allele shows a similar behavior, while in the second half cleft it displays a narrower and more flexible groove conformation in the presence of viral peptide. We further characterized these dynamical differences by evaluating H-bonds, hydrophobic and stacking interaction networks, finding striking similarities with super-type patterns emerging in other autoimmune diseases. The protective allele shows a defined preferential binding to myelin peptide, as confirmed by binding free energy calculations. All together, we believe the presented molecular analysis could help to design experimental assays, supports the molecular mimicry hypothesis and suggests that propensity to multiple sclerosis in Sardinia could be partly linked to distinct peptide-MHC interaction and binding characteristics of the antigen presentation mechanism.

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“…43) The conformational change of HLA molecule due to the peptide binding has been analyzed. [44][45][46] Such a conformational change was shown to be closely related to the recognition of the peptide-HLA complex by CTLs, 45) and the conformational difference between the peptide-bound and -unbound HLAs was clearly indicated by the removal of the bound peptide from a complex model. 46) Nojima et al investigated the structural changes of the peptide-binding groove due to the removal of the peptide using the normal mode analysis.…”

Section: )mentioning

confidence: 99%

Computational Analysis on the Binding of Epitope Peptide to Human Leukocyte Antigen Class I Molecule A*2402 Subtype

et al. 2011

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Major histocompatibility complex (MHC) is a transmembrane glycoprotein that plays an important role in immunological system. Human MHC molecule is usually called as human leukocyte antigen (HLA) and HLA molecules are grouped into class I and II. MHC class I molecule is a heterodimer of heavy chain called a chain, whose mass-weight is 45 kDa, and light chain called b2 micro globulin (b2m) with a mass-weight of 12 kDa. A complex of an HLA and a peptide derived from antigen is displayed on the surface of nucleated cell or platelet. HLA heavy chain has a quite large diversity and thousands of genes have been detected so far, and the number of known genes for HLA heavy chain is still increasing. Each individual has two or three kinds of HLA out of several thousands of HLA genes.Viral protein or cancer-related antigens are detected as foreign molecules in a cell and dissociated by proteasome into peptide fragments consisting of 6-15 amino residues.1) This peptide fragment is bound to HLA class I molecule and the complex is carried to the cell surface in antigen display cells. Cytotoxic T lymphocytes (CTL) expressing T cell receptor recognize the complex, which results in inducing the immunological response to attack the virus-infected or oncogenic cells to exclude virus or tumor. 2)Immunological response has attracted much recent attention because of its potential for immunotherapy. At present, several peptides are assumed to be effective for medical treatment of cancer, leukemia, hepatitis C, and applied to patients in a clinical trial as vaccine through the controlled vaccination.3-5) This peptide-vaccine therapy is expected to lead the regression of disease-related cells without damaging normal tissues. Since the combination of HLA genes has a large diversity, the selection of peptide adequate for each individual is one of the important issues to enhance the performance of immunotherapy.The discovery of a peptide inducing strong immunological response is a key factor in immunotherapy. Since the peptide firmly bound to HLA molecule will be effective as medical material, the search of potent peptide, usually called as epitope, is critically important. In this study, we focus on Wilms' tumor (WT1) protein.6) WT1 protein is encoded in b2 Wilms' tumor gene and overexpressed in leukemic and solid tumor cell. A 9-mer amino acid peptide encoded in WT1 protein was already known to work as an antigenic peptide for HLA-A*2402 molecule. Oka and his co-workers reported the experimental findings that the replacement of the second amino acid residue, which is considered to be deeply responsible for the peptide binding to HLA-A*2402, induced strong immunological response of WT1 specific CTLs compared to the natural peptide. A peptide containing a single amino residue mutation is currently applies for the clinical trial for a vaccination against solid tumor or leukemia. 7)Computer simulation enables us to visualize the interaction of proteins or the interaction of a chemical compound and its target protein. Molecular dynamics (MD) ...

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A Comparative Approach Linking Molecular Dynamics of Altered Peptide Ligands and MHC with In Vivo Immune Responses

Cited by 31 publications

References 30 publications

Association of HLA-DR1 with the allergic response to the major mugwort pollen allergen: molecular background

Association of HLA-DR1 with the allergic response to the major mugwort pollen allergen: molecular background

Structural and Dynamical Insights on HLA-DR2 Complexes That Confer Susceptibility to Multiple Sclerosis in Sardinia: A Molecular Dynamics Simulation Study

Computational Analysis on the Binding of Epitope Peptide to Human Leukocyte Antigen Class I Molecule A*2402 Subtype

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