Multiscale Modeling of Pilin Subunit Recognition by Pneumoccus Sortase C enzymes

描述（由申请人提供）：人类病原体肺炎链球菌是一种传染性病原体，每年在全世界造成数百万人死亡，特别是在年轻人和老年人中，并且是多种疾病的主要原因，包括细菌性肺炎，败血症和脑膜炎。这些革兰氏阳性细菌的毒力通过菌毛而增加，菌毛是细菌表面细长的纤维结构，在定植过程中介导细胞间粘附。C类分选酶（SrtC）是毛的构建者，它们通过识别毛蛋白亚基并将它们彼此共价连接而起作用。因此，SrtC活性与感染之间的直接联系为对常规治疗具有耐药性的肺炎球菌菌株提供了令人兴奋的新抗菌靶点。在这个应用中，我提出了一系列的生物分子模拟，以解决三种肺炎链球菌SrtC蛋白的毛蛋白亚基识别机制的远程结合和局部诱导配合结合机制，这是毛组装的重要初始步骤。这些研究得出的数据将在未来针对SrtC的基于结构的药物设计工作中证明是无价的。结果也将为我的长期目标奠定基础，即开发一个完整的pilin装配过程模型，以解决有关该过程的现有实验数据中的差异。获得K22奖不仅将为实现这些科学目标提供支持，而且对我未来独立的生物医学事业也将大有裨益。我的长期目标是在一流研究型大学建立一个充满活力、富有成效的研究小组，利用理论和计算技术，与实验学家密切合作，解决和推进我们对公共卫生重要问题的理解。在这个提案中，我提出了一个职业发展计划，它将指导我从一个受指导的科学家到一个独立的科学家，重点是技术和非技术技能的发展，这对我未来作为助理教授的职业生涯很重要。我期望利用这项拨款提供的两年支持来奠定科学的基础

DESCRIPTION (provided by applicant): The human pathogen Streptococcus pneumoniae is an infectious agent responsible for millions of deaths world- wide a year, particularly among the young and the elderly, and is the leading cause of multiple diseases, including bacterial pneumonia, sepsis, and meningitis. The virulence of these Gram-positive bacteria is increased by pili, elongated fibrous structures on their surface that mediate intercellular adhesion during the colonization process. Class C sortase enzymes (SrtC) are the architects of pili, and they function by recognizing and covalently linking pilin subunits to one another. This direct link between SrtC activity and infection therefore presents an exciting new antibacterial target for pneumococci strains that are resistant to conventional therapeutics. In this appli- cation, I propose a series of biomolecular simulations that address both the long-range association and local, induced-fit binding mechanisms of the pilin subunit recognition mechanism by each of the three S. pneumoniae SrtC proteins, important initial steps in the assembly of pili. Data resulting from these studies will prove invaluable in future structure-based drug design efforts that target SrtC. Results will also lay a foundation for my long term goal of developing a complete model of the pilin assembly process that would resolve discrepancies in the available experimental data concerning this process. Receipt of the K22 award will provide support in not only accomplishing these scientific goals, but will also greatly benefit my future independent biomedical career. My long term goals involve building a vibrant, productive research group at a Tier 1 research university that uses theoretical and computational techniques, in strong collaborations with experimentalists, to address and advance our understanding of issues important to public health. In this proposal I present a career development plan that will guide my transition from a mentored to an independent scientist that focuses on the development of technical and non-technical skills that will be important for my future career as an assistant professor. I anticipate using the two years of support provided by this grant to lay the scientific foundation necessary for creating future competitive applications, including other junior faculty awards and an R01 grant.