Multiscale Mechanics of Cell Interactions With Flexible Nanofilaments

柔性纳米丝是人造材料、活细胞和埃博拉病毒等病毒的基本组成部分。最近在西非爆发的埃博拉病毒病突显了纳米丝对人类健康的重要性，该疾病始于2013年，持续了两年多。因此，了解纳米丝如何进入活细胞对社会具有重要意义。该项目旨在了解柔性纳米丝如何相互作用并进入人类和动物细胞，从而帮助解决了解丝状病毒生命周期以及工程纳米材料潜在健康危害的迫切社会需求。这项研究的结果将有利于美国的经济和社会，因为工程纳米材料正在成为美国材料流动的重要组成部分，大多数人造纳米材料最终将被填埋，从而影响我们的生态系统和健康。该研究的多学科方法将对布朗大学的工程教育和推广活动产生积极影响。这些教育项目将为研究生和访问学者提供培训，并为本科生提供研究经验。这项工作将解决以下基本力学问题，这些问题是该领域大量实验观察的基础：(1)柔性纳米丝在细胞膜上的附着，(2)包裹纳米丝的膜的融合，(3)柔性纳米丝的生物包装，以及(4)纳米丝从细胞膜出芽。技术方法将基于PIs研究小组在细胞力学方面开发的一些理论和模拟技术。这项工作将通过理论建模和大尺度粗粒度分子动力学模拟蛋白质介导的黏附域成核，考虑受体扩散，结合动力学和膜波动，膜融合，重点关注包裹纳米丝的大小，形状和弯曲刚度的影响，以及脂质膜的组成，为纳米丝的细胞加工动力学提供有用的见解。测定纳米丝和丝网的细胞包装的相图与长度、弹性性能和纳米丝与细胞膜之间的相互作用，以及机械性能和细胞相互作用对纳米丝出芽模式的影响。工作中的超大规模模拟将在国家计算科学研究所进行，其余的计算工作将在布朗大学计算与可视化中心进行。

Flexible nanofilaments are fundamental components of man-made materials, living cells and of viruses such as Ebola. The importance to human health of nanofilaments is highlighted by the recent outbreak of Ebola virus disease in West Africa, which began in 2013 and continued for over two years. Understanding how nanofilaments enter living cells, therefore, has important relevance to society. This project is aimed to understand how flexible nanofilaments interact and enter human and animal cells, thereby helping address the urgent societal needs to understand the life cycle of filoviruses as well as the potential health hazards of engineered nanomaterials. Results from this research will benefit the U.S. economy and society, as engineered nanomaterials are becoming a significant fraction of material flows in the U.S. and most of the manufactured nanomaterials will eventually end up in landfills, hence impacting our ecosystem and health. The multi-disciplinary approach of the research will positively impact engineering education and outreach activities at Brown University. The educational programs will provide training for graduate students and visiting scholars, as well as research experience for undergraduate students. This work will address the following fundamental mechanics issues that underlie a vast variety of experimental observations in the field: (1) attachment of flexible nanofilaments onto a cell membrane, (2) fusion of membranes that envelop nanofilaments, (3) biopackaging of flexible nanofilaments, and (4) budding of nanofilaments from a cell membrane. The technical approaches will be based on a number of theoretical and simulation techniques developed by the PIs research group in cell mechanics. This work will provide useful insights into the kinetics of cell processing of nanofilaments through theoretical modeling and large scale coarse-grained molecular dynamics simulations of protein-mediated nucleation of adhesion domains with considerations of receptor diffusion, binding kinetics and membrane undulation, membrane fusion focusing on the effects of size, shape and bending rigidity of enveloped nanofilaments and compositions of lipid membranes, determination of phase diagrams of cell packaging of nanofilaments and filament networks with respect to the length, elastic properties and interaction between nanofilaments and cell membranes, and effects of mechanical properties and cell interactions on modes of nanofilament budding. The ultra-large scale simulations in the work will be performed at the National Institute for Computational Sciences, and the rest of the computational work will be performed at the Center for Computing and Visualization at Brown University.