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：
8581210
负责人：
Jeffery Wereszczynski
金额：
$ 15.77万
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 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8581210
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

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

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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）：人类病原体肺炎肺炎是一种传染病，造成数百万死亡的世界，尤其是年轻人和老年人，是多种疾病的主要原因，包括细菌性肺炎，败血症，败血症和脑膜炎。这些革兰氏阳性细菌的毒力通过pili增加，在其表面上伸长的纤维结构在定殖过程中介导细胞间粘附。 C类分类酶（SRTC）是PILI的建筑师，它们通过识别和共价将Pilin亚基相互连接而起作用。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。在此应用中，我提出了一系列生物分子模拟，该模拟通过三种肺炎链球菌SRTC蛋白中的每个链球菌蛋白中的每一个，均应解决PILIN亚基识别机制的局部诱导结合机制，这是PILI组装的重要初始步骤。这些研究产生的数据将证明是针对SRTC的未来基于结构的药物设计工作的宝贵的。结果还将为我的长期目标奠定基础，即开发PILIN组装过程的完整模型，该过程将解决有关此过程的可用实验数据中的差异。获得K22奖的收到将不仅为实现这些科学目标提供支持，而且还将极大地使我未来的独立生物医学生涯受益。我的长期目标涉及在1级研究大学建立一个充满活力的，生产性的研究小组，该研究使用理论和计算技术，与实验者进行了强有力的合作，以解决和促进我们对对公共卫生重要问题的理解。在此提案中，我提出了一项职业发展计划，该计划将指导我从一个指导的独立科学家的过渡，重点是发展技术和非技术技能，这对我作为助理教授的未来职业至关重要。我预计会利用这笔赠款提供的两年支持来奠定科学创建未来竞争应用所必需的基金会，包括其他初级教师奖和R01赠款。