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

噬菌体是感染细菌的病毒，它们是地球上数量最多的生物体。噬菌体T4通过一个惊人的蛋白质机器将其DNA注入宿主体内，这生动地说明了它们也是利用机械原理的复杂机器。这项研究将回答关于如何使用新颖的计算建模方法注射机械工作的基本问题。通过先进的建模和仿真方法，计算模型将揭示整个高动态注入过程的细节，这些建模和仿真方法比目前的方法具有更长的时间和空间尺度，并且具有更详细的信息。这项研究位于机械工程、分子生物物理学和计算科学的交叉点，对纳米技术的进步具有直接影响，纳米技术旨在利用病毒机制为人类健康提供有用的目的。该研究将结合连续模型和大规模全原子分子动力学模拟，以获得一个多尺度模型，以捕获T4注射机械的动力学。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）和全局（连续体）表示的新耦合中出现，包括为注射提供动力的柔性鞘结构，穿透宿主（大肠杆菌）的中央尾管，以及由于病毒衣壳（头部）上的流体动力和宿主在尾管尖端的相互作用而产生的调节作用。基于该多尺度模型的模拟将揭示注射的生物时间尺度，生成尾部收缩的动力学途径，解释驱动注射的蓄能机制，并预测驱动尾部进入宿主细胞的力。单独来说，这些都代表了在机制水平上理解病毒感染科学的重大贡献。这些贡献也可能使病毒在纳米技术应用中的应用取得未来的进展，包括门控、传感、易位、肽展示和噬菌体治疗。此外，该项目将对两名创建多尺度模型的博士生和一组构建T4注射机械工作力学模型的本科生的教育产生积极影响。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，在密歇根州伊普斯兰蒂的亚当斯学院开展工程主题课程，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学生的合作机构传播模拟结果，从而吸引更广泛的公众。

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.