CDS&E/Collaborative Research: Exposing the Injection Machinery Dynamics of Bacteriophage T4 through Multi-Scale Modeling

CDS

• 批准号: 1404747
• 负责人: Noel Perkins
• 金额: $ 27.04万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1404747&HistoricalAwards=false
• 关键词: CDS& Collaborative; Research; Exposing; Injection

Bacteriophages are viruses that infect bacteria and they are the most abundant organisms on our planet. They are also sophisticated machines that exploit mechanics as vividly illustrated by bacteriophage T4 which injects its DNA into a host through an amazing protein machine. This research will answer fundamental questions regarding how the injection machinery works using novel computational modeling methods. The computational models will expose details of the entire, highly dynamic injection process by advancing modeling and simulation methods for longer time and space scales and with greater detail than current approaches. This research, which lies at the intersection of mechanical engineering, molecular biophysics and computational science, has direct implications to advances in nanotechnologies which aim to harness viral machinery for useful purposes for human health.The research will combine continuum models and large scale all-atom molecular dynamics simulations to arrive at a multi-scale model that captures the dynamics of the T4 injection machinery. In particular, the multi-scale model will emerge from a novel coupling of local (atomistic) and global (continuum) representations of the major protein domains of the injection machinery, including the flexible sheath structure which powers injection, the central tail tube that penetrates the host (E. coli), and the modulating effects due to hydrodynamic forces on the viral capsid (head) and the interaction forces of the host on the tip of the tail tube. Simulations based on this multi-scale model will reveal the biological time scale of injection, generate dynamical pathways for tail contraction, explain the stored energy mechanism driving injection, and predict the forces responsible for driving the tail into the host cell. Individually, these represent major contributions in understanding the science of virus infection at a mechanistic level. These contributions may also enable future advances in the use of viruses in nanotechnology applications ranging from gating, sensing, translocation, peptide display, and phage therapy. In addition, this project will positively impact the education of two doctoral students who will create the multi-scale model and a team of undergraduate students who will construct a working mechanical model of the T4 injection machinery. The project will also engage the broader public by featuring results at scientific workshops, educating graduate students and postdocs in the Mathematical and Computational Biology Gateway Program at UC-Irvine, conducting engineering-themed lessons at Adams Academy in Ypsilanti, Michigan, and disseminating simulation results through the Computational Modeling Facility at UC-Irvine and to two partner institutions with large URM student populations.

噬菌体是感染细菌的病毒，它们是我们星球上最丰富的生物体。它们也是利用机械原理的复杂机器，正如噬菌体T4生动地说明的那样，噬菌体T4通过一个惊人的蛋白质机器将其DNA注入宿主。这项研究将回答有关注射机械如何使用新的计算建模方法的基本问题。计算模型将揭示整个高度动态的注射过程的细节，通过先进的建模和模拟方法，在更长的时间和空间尺度上，比目前的方法更详细。这项研究处于机械工程、分子生物物理学和计算科学的交叉点，对纳米技术的进步有直接影响，纳米技术旨在利用病毒机制为人类健康服务。该研究将结合连续介质模型和大规模全原子分子动力学模拟，以获得捕捉T4注射机制动力学的多尺度模型。联合收割机。特别是，多尺度模型将出现从一个新的耦合的局部（原子）和全球（连续）表示的主要蛋白质结构域的注射机制，包括灵活的鞘结构的权力注射，中央尾管，穿透主机（E。大肠杆菌），以及由于对病毒衣壳（头部）的流体动力和宿主对尾管尖端的相互作用力而产生的调节作用。 基于该多尺度模型的模拟将揭示注射的生物时间尺度，产生尾部收缩的动力学途径，解释驱动注射的储能机制，并预测负责将尾部驱动到宿主细胞中的力。个别地，这些代表在理解病毒感染的科学在一个机械水平上的主要贡献。这些贡献也可能使未来的进步，在纳米技术应用中使用的病毒，从门控，传感，易位，肽展示和噬菌体治疗。此外，该项目将对两名博士生的教育产生积极影响，他们将创建多尺度模型，一个本科生团队将构建T4注塑机的工作机械模型。 该项目还将通过在科学研讨会上展示结果，在加州大学欧文分校的数学和计算生物学门户项目中教育研究生和博士后，在密歇根州伊普西兰蒂的亚当斯学院进行以工程为主题的课程，并通过加州大学欧文分校的计算建模设施和两个拥有大量URM学生人口的合作机构传播模拟结果，来吸引更广泛的公众。