Multiscale Modeling of Pilin Subunit Recognition by Pneumoccus Sortase C enzymes

描述(申请人提供)：人类病原体肺炎链球菌是一种感染性病原体，每年在全球范围内造成数百万人死亡，特别是在年轻人和老年人中，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因其表面的细长纤维结构而增强，这种结构在定植过程中介导细胞间的粘连。C类分类酶(SrtC)是菌毛的设计者，它们通过识别和共价连接菌毛蛋白亚基而发挥作用。因此，srtC活性和感染之间的这种直接联系为对传统疗法耐药的肺炎球菌菌株提供了一个令人兴奋的新的抗菌靶。在这一应用中，我提出了一系列生物分子模拟，以解决三个肺炎链球菌SrtC蛋白对菌毛蛋白亚单位识别机制的远程结合和局部诱导结合机制，这是组装菌毛的重要初始步骤。这些研究产生的数据将在未来针对SrtC的基于结构的药物设计工作中被证明是非常宝贵的。结果也将为我的长期目标奠定基础，即开发一个完整的毛细管组装过程模型，以解决有关这一过程的现有实验数据中的差异。K22奖的获得不仅将为实现这些科学目标提供支持，也将极大地有利于我未来的独立生物医学职业生涯。我的长期目标包括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，该小组使用理论和计算技术，与实验者密切合作，解决和促进我们对公共卫生重要问题的理解。在这份提案中，我提出了一项职业发展计划，该计划将指导我从一名受指导的科学家转变为一名独立科学家，专注于发展对我未来的助理教授职业生涯至关重要的技术和非技术技能。我期待着利用这笔赠款提供的两年支持来为科学 为创建未来竞争性应用程序所必需的基础，包括其他初级教师奖和R01补助金。

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.