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

由I类主要组织相容性复合体（I类MHC）编码的蛋白质负责将抗原（8-12个氨基酸的小肽）结合和“呈递”至细胞毒性T细胞。该蛋白是由重链、肽和小亚基b2-微球蛋白（b2 m）组成的异源三聚体复合物。尽管I类肽/MHC复合物在免疫系统中的核心作用和多年的关键研究，重要的问题仍然是这些分子如何组装，组装复合物的物理性质，以及肽结合如何与序列，结构和生物活性相关。这个CAREER项目描述了一项针对这些缺口的I类肽/MHC复合物的研究。通过利用最新的进展，允许无肽MHC分子及其与肽的相互作用的表征，本项目的工作将1）产生肽结合，蛋白质结构和生物活性之间的相关性，2）表征蛋白质构象动力学和肽识别之间的联系，3）研究肽结合沟中的残留肽动力学。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，可以建立更严格的预测和设计具有所需亲和力和生物活性的肽的策略。结果也将适用于更基本的问题，有关蛋白质动力学，蛋白质折叠连接到绑定，用于识别小的灵活的配体的策略，和组装的多亚基复合物。本CAREER项目建议书的教育和培训部分反映了其分子生物物理学重点的研究部分。最近开发的分子生物物理学研究生/高年级本科生课程将得到加强，并选择生物物理概念将在化学和生物化学系的生物化学本科生核心课程强调。为了加强校内的培训和合作，将成立一个跨部门的分子生物物理学兴趣小组，其长期目标是形成一个正式的培训计划。最后，在认识到希望增加机会，在科学的代表性不足的少数民族，非正式安排已与教师在教育部指定的少数民族机构，以协助增加入学人数不足的少数民族在圣母大学研究生生物化学方案。

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.