title: A comparative approach linking molecular dynamics of altered peptide ligands and MHC with in vivo immune responses.
abstract: BACKGROUND
  The recognition of peptide in the context of MHC by T lymphocytes is a critical step in the initiation of an adaptive immune response. However, the molecular nature of the interaction between peptide and MHC and how it influences T cell responsiveness is not fully understood.
  
  
  RESULTS
  We analyzed the immunological consequences of the interaction of MHC class II (I-Au) restricted 11-mer peptides of myelin basic protein with amino acid substitutions at position 4. These mutant peptides differ in MHC binding affinity, CD4+ T cell priming, and alter the severity of peptide-induced experimental allergic encephalomyelitis. Using molecular dynamics, a computational method of quantifying intrinsic movements of proteins at high resolution, we investigated conformational changes in MHC upon peptide binding. We found that irrespective of peptide binding affinity, MHC deformation appears to influence costimulation, which then leads to effective T cell priming and disease induction. Although this study compares in vivo and molecular dynamics results for three altered peptide ligands, further investigation with similar complexes is essential to determine whether spatial rearrangement of peptide-MHC and costimulatory complexes is an additional level of T cell regulation.
authors.affiliation: Department for Biomedical Computer Simulation and Bioinformatics, Medical University of Vienna, Vienna, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Knapp
authors.forename: Ulrich
authors.initials: U
authors.lastname: Omasits
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schreiner
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Epstein
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D056004:Molecular Dynamics Simulation; D004676:Myelin Basic Protein / Q000737:chemistry; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects
chemical_list: D000949:Histocompatibility Antigens Class II; D008024:Ligands; D004676:Myelin Basic Protein; D010455:Peptides