The Carboxy Terminus of the Ligand Peptide Determines the Stability of the MHC Class I Molecule H-2Kb: A Combined Molecular Dynamics and Experimental Study.
Major histocompatibility complex (MHC) class I molecules (proteins) bind peptides of eight to ten amino acids to present them at the cell surface to cytotoxic T cells. The class I binding groove binds the peptide via hydrogen bonds with the peptide termini and via diverse interactions with the anchor residue side chains of the peptide. To elucidate which of these interactions is most important for the thermodynamic and kinetic stability of the peptide-bound state, we have combined molecular dynamics simulations and experimental approaches in an investigation of the conformational dynamics and binding parameters of a murine class I molecule (H-2Kb) with optimal and truncated natural peptide epitopes. We show that the F pocket region dominates the conformational and thermodynamic properties of the binding groove, and that therefore the binding of the C terminus of the peptide to the F pocket region plays a crucial role in bringing about the peptide-bound state of MHC class I.
Department of Chemistry and Life Sciences, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany; Department of Physics, Faculty of Science, Ain Shams University, Cairo, Egypt.
Esam Tolba
ET
Abualrous
Department of Chemistry and Life Sciences, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany.
Sunil Kumar
SK
Saini
Department of Chemistry and Life Sciences, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany.
Venkat Raman
VR
Ramnarayan
Department of Chemistry and Life Sciences, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany.
Florin Tudor
FT
Ilca
Physik-Department T38, Technische Universität München, James-Franck-Strasse 1, 85748 Garching, Germany.
Martin
M
Zacharias
Department of Chemistry and Life Sciences, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany.
Sebastian
S
Springer
D000818:Animals; D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006183:H-2 Antigens / Q000737:chemistry* / Q000276:immunology; D008024:Ligands; D051379:Mice; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000276:immunology
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D008024:Ligands; D010455:Peptides