CAREER: Assembly and Dynamics of Class I Peptide/MHC Complexes

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The protein encoded by the class I major histocompatibility complex (class I MHC) is responsible for binding and "presenting" antigens, small peptides of 8-12 amino acids, to cytotoxic T cells. The protein is a heterotrimeric complex consisting of a heavy chain, peptide, and the small subunit b2-microglobulin (b2m). Despite the central role of class I peptide/MHC complexes in the immune system and many years of critical study, important questions remain about how these molecules assemble, the physical properties of the assembled complex, and how peptide binding correlates with sequence, structure, and biological activity. This CAREER project describes a study of class I peptide/MHC complexes that addresses these gaps. By taking advantage of recent advances allowing characterization of peptide-free MHC molecules and their interactions with peptides, the work in this project will 1) generate correlations between peptide binding, protein structure, and biological activity, 2) characterize the link between protein conformational dynamics and peptide recognition, and 3) investigate residual peptide dynamics in the peptide-binding groove. The results will be of significant interest to those interested in the functional and physical properties of these important molecules. They will provide data on which more rigorous strategies for the prediction and design of peptides with desired affinity and biological activity can be built. The results will also be applicable to more basic questions related to protein dynamics, protein folding linked to binding, strategies used for the recognition of small flexible ligands, and the assembly of multi-subunit complexes. The education and training component of this CAREER project proposal mirrors the research component in its focus on molecular biophysics. A recently developed graduate/senior undergraduate course in molecular biophysics will be enhanced, and select biophysical concepts will be emphasized in the Department of Chemistry and Biochemistry's core curriculum for biochemistry undergraduates. To enhance on-campus training and collaboration, an interdepartmental interest group in molecular biophysics will be formed, with the long-term goal of forming a formal training program. Finally, in recognition of the desire to enhance opportunities in science for under-represented minorities, informal arrangements have been made with faculty at a Department of Education-designated Minority Institution to assist in increasing enrollment of under-represented minorities in the University of Notre Dame graduate biochemistry program.