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。它们也是精致的机器，利用了噬菌体T4生动地说明的机制，它通过惊人的蛋白质机将其DNA注入宿主。这项研究将回答有关注射机械如何使用新型计算建模方法运作的基本问题。计算模型将通过在更长的时间和空间尺度上推进建模和仿真方法来揭示整个高度动态注入过程的细节，并且具有比当前方法更大的详细信息。这项研究位于机械工程，分子生物物理学和计算科学的相交，对纳米技术的进展有直接影响，旨在利用病毒机械来实现人类健康的有用目的。该研究将结合连续性模型和大规模的全部分子动力学模拟，以捕获跨度模型，以捕获动力学，以捕获动态的构图。特别是，多尺度模型将从注射机械的主要蛋白质结构域的局部（原子）和全球（连续性）表示的新型耦合中出现，包括柔性鞘内的柔性鞘内结构，中央尾管的中央尾管渗透到宿主（E. coli），以及均应触发的尖端效果（均可体现），并构成了对象征的影响（均具有较大的动力），并均置于象征性的范围（均具有较大的象征）。 管子。 基于此多尺度模型的模拟将揭示注射的生物时间尺度，生成尾部收缩的动力途径，解释储存的能量机制驱动注入，并预测负责将尾巴驱动到宿主细胞的力。单独地，这些代表了理解机械水平病毒感染科学的主要贡献。这些贡献还可以使未来在纳米技术应用中使用病毒的进展，从门控，感应，易位，肽显示和噬菌体疗法等等。此外，该项目将对两个博士生的教育产生积极影响，他们将创建多尺度模型和一组本科生的团队，这些学生将建立T4注入机械的机械模型。 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.