title: The Thermodynamic Mechanism of Peptide-MHC Class II Complex Formation Is a Determinant of Susceptibility to HLA-DM.
abstract: Peptides bind MHC class II molecules through a thermodynamically nonadditive process consequent to the flexibility of the reactants. Currently, how the specific outcome of this binding process affects the ensuing epitope selection needs resolution. Calorimetric assessment of binding thermodynamics for hemagglutinin 306-319 peptide variants to the human MHC class II HLA-DR1 (DR1) and a mutant DR1 reveals that peptide/DR1 complexes can be formed with different enthalpic and entropic contributions. Complexes formed with a smaller entropic penalty feature circular dichroism spectra consistent with a non-compact form, and molecular dynamics simulation shows a more flexible structure. The opposite binding mode, compact and less flexible, is associated with greater entropic penalty. These structural variations are associated with rearrangements of residues known to be involved in HLA-DR (DM) binding, affinity of DM for the complex, and complex susceptibility to DM-mediated peptide exchange. Thus, the thermodynamic mechanism of peptide binding to DR1 correlates with the structural rigidity of the complex, and DM mediates peptide exchange by "sensing" flexible complexes in which the aforementioned residues are rearranged at a higher frequency than in more rigid ones.
authors.affiliation: Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK 99775; aferrante@alaska.edu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ferrante
authors.affiliation: Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK 99775; Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, AK 99775; and.
authors.forename: Megan
authors.initials: M
authors.lastname: Templeton
authors.affiliation: Department of Veterinary Medicine, University of Alaska Fairbanks, Fairbanks, AK 99775.
authors.forename: Megan
authors.initials: M
authors.lastname: Hoffman
authors.affiliation: Department of Veterinary Medicine, University of Alaska Fairbanks, Fairbanks, AK 99775.
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Castellini
mesh_terms: D002942:Circular Dichroism; D006681:HLA-D Antigens / Q000276:immunology / Q000378:metabolism*; D015798:HLA-DR1 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006388:Hemagglutinins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D020349:Surface Plasmon Resonance; D013696:Temperature; D013816:Thermodynamics
chemical_list: D006681:HLA-D Antigens; C084245:HLA-DM antigens; D015798:HLA-DR1 Antigen; D006388:Hemagglutinins