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Multiscale Modeling of Pilin Subunit Recognition by Pneumoccus Sortase C enzymes

肺炎球菌分选酶 C 酶识别菌毛蛋白亚基的多尺度模型

基本信息

批准号：
8707965
负责人：
Jeffery Wereszczynski
金额：
$ 10.35万
依托单位：
ILLINOIS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8707965
关键词：
Accounting Active Sites Address Adhesions Anti-Bacterial Agents Applications Grants Award Bacteria Bacterial Pneumonia Binding Cations Cessation of life Child Collaborations Collection Communicable Diseases Computational Technique Computer Simulation Data Development Development Plans Disease Drug Design Elderly Electrostatics Environment Enzymes Extracellular Structure Faculty Fimbriae Proteins Foundations Free Energy Frequencies Future Goals Gram-Positive Bacteria Grant Human Infection Infectious Agent K22 Award Knowledge Lead Length Link Mediating Meningitis Mentors Modeling Motion Mutation Pathway interactions Phase Pilum Play Pneumonia Process Property Proteins Protocols documentation Psychological Techniques Public Health Research Resistance Role Sampling Scientist Sepsis Series Signal Transduction Sorting - Cell Movement Specificity Staphylococcus aureus Streptococcus pneumoniae Structure Surface Techniques Therapeutic Thermodynamics Time Training Universities Validation Variant Virulence Work base career career development crosslink experience improved insight molecular dynamics multi-scale modeling pathogen professor public health relevance resistant strain simulation skills sortase

项目摘要

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.

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，每年导致全球数百万人死亡，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。这些革兰氏阳性菌的毒力通过皮利而增加，所述菌毛是其表面上的细长纤维结构，其在定殖过程中介导细胞间粘附。C类分选酶（SrtC）是皮利的建筑师，并且它们通过识别并共价连接菌毛蛋白亚基而起作用。因此，SrtC活性与感染之间的这种直接联系为对常规疗法具有抗性的肺炎球菌菌株提供了令人兴奋的新抗菌靶标。在这个应用中，我提出了一系列的生物分子模拟，解决了远程协会和本地，诱导适合的菌毛蛋白亚基识别机制的三个S。肺炎SrtC蛋白，组装皮利的重要初始步骤。从这些研究中得到的数据将证明是非常宝贵的，在未来的结构为基础的药物设计工作，目标SrtC。研究结果也将为我的长期目标奠定基础，即开发一个完整的菌毛蛋白组装过程的模型，以解决有关这一过程的现有实验数据的差异。获得K22奖不仅将为实现这些科学目标提供支持，而且还将大大有利于我未来的独立生物医学事业。我的长期目标是在一级研究型大学建立一个充满活力，富有成效的研究小组，该研究小组使用理论和计算技术，与实验学家密切合作，以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，我提出了一个职业发展计划，将指导我从一个指导过渡到一个独立的科学家，专注于技术和非技术技能的发展，这将是我未来的职业生涯作为一个助理教授的重要。我希望利用这笔赠款提供的两年支持，创建未来竞争力的应用程序所需的基础，包括其他初级教师奖和R01补助金。