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

由第I类主要组织相容性复合体(第I类MHC)编码的蛋白质负责结合并向细胞毒性T细胞递送抗原，即8-12个氨基酸的小肽。该蛋白质是由重链、多肽和小亚单位b2-微球蛋白(B2M)组成的异三聚体复合体。尽管I类肽/MHC复合体在免疫系统中起着核心作用，经过多年的关键研究，但这些分子是如何组装的，组装的复合体的物理性质，以及肽结合如何与序列、结构和生物活性相关联，仍然是重要的问题。这个职业项目描述了一项针对I类多肽/MHC复合体的研究，以解决这些差距。通过利用最近对无肽MHC分子及其与多肽的相互作用的表征，本项目的工作将1)建立多肽结合、蛋白质结构和生物活性之间的关联，2)表征蛋白质构象动力学和多肽识别之间的联系，3)研究多肽结合槽中的残余多肽动力学。这些结果将对那些对这些重要分子的功能和物理性质感兴趣的人产生重大兴趣。他们将提供数据，在此基础上建立更严格的预测和设计具有所需亲和力和生物活性的多肽的策略。这些结果也将适用于与蛋白质动力学有关的更基本的问题，与结合有关的蛋白质折叠，用于识别小分子柔性配体的策略，以及多亚单位复合体的组装。这项职业项目提案的教育和培训部分反映了其重点是分子生物物理学的研究部分。将加强最近开发的分子生物物理学研究生/高级本科课程，并在化学和生物化学系面向生物化学本科生的核心课程中强调选定的生物物理概念。为了加强在校培训和协作，将成立一个跨部门的分子生物物理学兴趣小组，长期目标是形成正式的培训计划。最后，认识到希望为代表不足的少数群体提供更多科学机会的愿望，与教育部指定的少数群体机构的教职员工作出了非正式安排，以协助圣母大学生物化学研究生项目招收代表不足的少数群体。

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.