Multiscale Modeling of Coronavirus Virions in the Respiratory System

非技术摘要新冠肺炎传播的方式之一是吸入含有冠状病毒SARS-CoV-2的小液滴。为了引起感染，病毒必须首先从呼吸道穿过一层分子厚度，即肺表面活性物质膜，进入肺部。由于冠状病毒和肺表面活性物质膜不断地相互影响和重塑，所以通过肺表面活性物质膜的过程并不是很清楚。肺表面活性物质膜是一种复杂而脆弱的纳米生物材料，主要由表面活性物质分子组成。某些类型的表面活性分子能够破坏和分解冠状病毒。这一能力可能被外源表面活性物质的医疗管理用于表面活性物质治疗，这目前正作为一种新冠肺炎治疗方法在临床试验中进行测试。该奖项支持计算研究和教育活动，在分子水平上详细研究SARS-CoV-2及其变种如何附着在肺表面活性物质膜上，病毒颗粒如何能够通过膜，以及表面活性物质分子如何影响这一过程。应用被称为分子动力学的计算研究方法，目的是了解肺表面活性物质层和相关冠状病毒颗粒的材料特性如何产生病理生理行为。以材料为中心的方法将这项研究置于凝聚态物理和生物学之间。在更广泛的影响中，有可能通过使用外源表面活性物质来寻找抑制冠状病毒活性的新的治疗途径。该项目的教育和指导方面包括培训来自不同背景的研究生和本科生，以及开发关于复杂生物纳米系统建模的教学模块。开发的模拟代码将通过精选的数据储存库向科学界提供。技术概述新冠肺炎通过吸入空气传播的冠状病毒颗粒SARS-CoV-2传播，SARS-CoV-2会渗透到呼吸系统并导致严重急性呼吸综合征(SARS)，可导致肺衰竭。SARS-CoV-2病毒粒子是球形纳米粒子，具有直径约85纳米的双层脂膜，上面装饰着由20纳米长的尖峰蛋白突起组成的“皇冠”。虽然我们对SARS-CoV-2的生化结构和功能的了解正在迅速增长，但作为纳米粒子与呼吸系统环境相互作用的病毒粒子的界面特性尚未得到解决，也知之甚少。弥合这一知识差距对于通过应用外源表面活性物质治疗SARS的临床研究具有重要意义。本项目旨在利用多尺度分子动力学模拟来探索SARS-CoV-2病毒粒子与肺表面活性物质膜相互作用的基本机制及其在呼吸系统中的去向。将SARS-CoV-2病毒粒子和肺表面活性物质膜视为在呼吸系统环境中相互作用的纳米级多功能生物材料代表了该项目的主要方法新颖性。PI将(A)开发原始的SARS-CoV-2病毒粒子和肺表面活性物质膜的粗粒计算模型，(B)建立SARS-CoV-2病毒粒子与肺表面活性物质膜和外源生物表面活性剂界面相互作用的分子机制，以及(C)探索这些相互作用对肺表面活性物质膜稳定性和SARS-CoV-2病毒粒子在呼吸系统中的去向的影响。该项目将建立涉及SARS-CoV-2变种的界面过程的多尺度计算模型，以解决目前尚未解决的问题：(1)肺表面活性物质脂质和蛋白质的吸附如何影响包膜和刺突蛋白，(2)SARS-CoV-2病毒粒子如何影响肺表面活性物质膜的完整性和稳定性，(3)洗涤剂活性以及肺和外源表面活性物质的吸附是否可以诱导病毒被膜的溶解，以及(4)肺表面活性物质与变异的SARS-CoV-2病毒粒子相互作用的特异性差异可能在多大程度上解释为什么一些冠状病毒变种比其他变种引起更多的感染和更快的传播。将特别注意SARS-CoV-2变异株在肺表面活性物质和外源性表面活性物质的粘附性方面的差异。对这些问题的回答将促进对SARS-CoV-2病毒粒子和肺表面活性物质作为相互作用的纳米生物材料的基本理解，并可能对预防和治疗新冠肺炎的外源性表面活性物质的选择具有临床意义。PI预计，该项目将通过推进对冠状病毒病毒粒子在肺环境中的病理生理行为和去向、表面活性诱导的病毒活性抑制以及合成病毒类型药物载体纳米颗粒通过细胞膜和其他生理界面的黏附和转移的计算研究，产生跨学科的变革影响。这项拟议的研究将支持多样性，培训研究生和本科生，并制作复杂生物纳米系统建模的模块。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

NONTECHNICAL SUMMARY One of the ways COVID-19 spreads is by breathing in small liquid droplets that contain the coronavirus SARS-CoV-2. In order to cause an infection, the virus must first pass from the respiratory tract through a layer of molecular thickness, the lung surfactant film, into the lung. The passage through the lung surfactant film is a process that is not well understood because the coronavirus and lung surfactant film continuously affect and remodel each other. The lung surfactant film is a complex and fragile nanoscale biomaterial that consists mostly of surfactant molecules. Certain types of surfactant molecules are capable of destabilizing and breaking up the coronavirus. This capability may be utilized by the medical administration of exogenous surfactants in surfactant therapy, which is currently being tested in clinical trials as a COVID-19 treatment approach. This award supports computational research and educational activities to study in detail and on a molecular level how SARS-CoV-2 and its variants adhere to the lung surfactant film, how the virus particle is capable of passing through the film, and how surfactant molecules affect this process. The computational research method, known as molecular dynamics, is applied with the goal to learn how pathophysiological behavior can emerge from the material properties of lung surfactant layer and associated coronavirus particles. The materials-centric approach places this research at the interface between condensed matter physics and biology. Among the broader impacts is the potential to inform the search for novel therapeutic pathways that inhibit coronavirus activity by using exogenous surfactants. Educational and mentoring aspects of this project include training graduate and undergraduate students from diverse backgrounds and developing teaching modules on the modeling of complex biological nanoscale systems. The developed simulation codes will be made available for the scientific community through curated data repositories. TECHNICAL SUMMARY COVID-19 is transmitted by inhaling airborne coronavirus particles, SARS-CoV-2, which penetrate the respiratory system and cause severe acute respiratory syndrome (SARS) that can lead to lung failure. SARS-CoV-2 virions are spheroidal nanoparticles, with a lipid bilayer envelope of about 85 nanometer diameter decorated by a “crown” of 20 nanometer long spike protein protrusions. Whereas our knowledge of the biochemical structure and functions of SARS-CoV-2 is quickly growing, the interfacial properties of the virions, as nanoparticles interacting with the respiratory system environment, have not been addressed and are poorly understood. Bridging this knowledge gap is important for informing clinical studies on surfactant therapies to treat SARS by administering exogenous surfactants. This project aims at using multiscale molecular dynamics simulations to explore the fundamental mechanisms of interactions of SARS-CoV-2 virions with lung surfactant films and their fate in the respiratory system. Consideration of SARS-CoV-2 virions and the lung surfactant film as nanoscale multifunctional biomaterials that interact within the respiratory system environment represents the main methodological novelty of the project. The PI will (a) develop original coarse-grained computational models of SARS-CoV-2 virions and lung surfactant films, (b) establish in-silico the molecular mechanisms of the SARS-CoV-2 virion interfacial interactions with lung surfactant films and exogenous biosurfactants, and (c) explore the effects of these interactions on the stability of lung surfactant films and the fate of SARS-CoV-2 virions in the respiratory system. The project will produce multiscale computational models of interfacial processes involving SARS-CoV-2 variants to address the currently unresolved questions: (1) how sorption of lung surfactant lipids and proteins affects the envelope membrane and spike proteins, (2) how SARS-CoV-2 virions affect the integrity and stability of lung surfactant films, (3) if detergent activity and sorption of pulmonary and exogenous surfactants can induce lysis of the viral envelope, and (4) to what extent the difference in specifics of lung surfactant interactions with mutated SARS-CoV-2 virions may explain why some coronavirus variants cause more infections and spread faster than others. Special attention will be paid to the differences between SARS-CoV-2 variants with respect to adhesion of pulmonary and exogenous surfactants. Answers to these questions will advance fundamental understanding of SARS-CoV-2 virions and lung surfactant films as interacting nanoscale biomaterials and may have clinical implications for the selection of exogenous surfactants for prophylaxis and treatment of COVID-19. The PI expects the project will have an interdisciplinary transformative impact by advancing computational studies of pathophysiological behavior and fate of coronavirus virions in pulmonary environment, surfactant-induced inhibition of the viral activity, as well as adhesion and translocation of synthetic virion-type drug carrier nanoparticles through cell membranes and other physiological interfaces. The proposed research will support diversity, train graduate and undergraduate students, and produce modules on the modeling of complex biological nanoscale systems.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.