Multiscale Modeling of Coronavirus Virions in the Respiratory System

呼吸系统中冠状病毒病毒颗粒的多尺度建模

• 批准号: 2138052
• 负责人: Alexander Neimark
• 金额: $ 49.98万
• 依托单位: Rutgers University New Brunswick
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2138052&HistoricalAwards=false
• 关键词: Multiscale; Modeling; Coronavirus; Virions; Respiratory

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.

COVID-19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通过一层分子厚度的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相互影响和重塑，通过肺表面活性物质膜的过程尚不清楚。肺表面活性剂膜是一种复杂而脆弱的纳米级生物材料，主要由表面活性剂分子组成。某些类型的表面活性剂分子能够破坏和分解冠状病毒。这种能力可用于表面活性剂治疗中外源性表面活性剂的医学管理，目前正在临床试验中作为COVID-19治疗方法进行测试。该奖项支持计算研究和教育活动，以便在分子水平上详细研究SARS-CoV-2及其变体如何粘附在肺表面活性剂薄膜上，病毒颗粒如何能够穿过薄膜，以及表面活性剂分子如何影响这一过程。应用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本研究置于凝聚态物理学和生物学之间的界面。在更广泛的影响中，有可能为寻找通过使用外源性表面活性剂抑制冠状病毒活性的新治疗途径提供信息。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，并开发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管理的数据存储库提供给科学界。COVID-19通过吸入空气中的冠状病毒颗粒SARS- cov -2传播，该颗粒可穿透呼吸系统，引起可导致肺衰竭的严重急性呼吸综合征（SARS）。SARS-CoV-2病毒粒子是球状纳米粒子，具有直径约85纳米的脂质双层包膜，由20纳米长的刺状蛋白突起组成的“冠”装饰。尽管我们对SARS-CoV-2的生化结构和功能的了解正在迅速增长，但病毒粒子作为与呼吸系统环境相互作用的纳米颗粒的界面特性尚未得到解决，而且了解很少。弥合这一知识差距对于通过施用外源性表面活性剂治疗SARS的表面活性剂疗法的临床研究具有重要意义。本项目旨在通过多尺度分子动力学模拟，探讨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命运。考虑到SARS-CoV-2病毒粒子和肺表面活性剂薄膜作为纳米级多功能生物材料，在呼吸系统环境中相互作用，代表了该项目在方法上的主要新颖之处。该项目将(a)建立SARS-CoV-2病毒粒子和肺表面活性剂膜的原始粗粒度计算模型，(b)通过计算机建立SARS-CoV-2病毒粒子与肺表面活性剂膜和外源性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剂膜稳定性和SARS-CoV-2病毒粒子在呼吸系统中的命运的影响。该项目将建立涉及SARS-CoV-2变体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)肺表面活性剂脂质和蛋白质的吸附如何影响肺表面活性剂膜和刺突蛋白；(2)SARS-CoV-2病毒粒子如何影响肺表面活性剂膜的完整性和稳定性；(3)肺表面活性剂和外源性表面活性剂的洗涤剂活性和吸附是否会诱导病毒包膜的裂解。(4)肺表面活性剂与突变的SARS-CoV-2病毒粒子相互作用的特异性差异在多大程度上可以解释为什么一些冠状病毒变体比其他冠状病毒变体引起更多感染和传播速度更快。将特别注意SARS-CoV-2变体在肺表面活性剂和外源性表面活性剂粘附方面的差异。这些问题的答案将促进对SARS-CoV-2病毒粒子和肺表面活性剂薄膜作为相互作用的纳米级生物材料的基本理解，并可能对选择外源性表面活性剂预防和治疗COVID-19具有临床意义。PI预计该项目将通过推进冠状病毒粒子在肺环境中的病理生理行为和命运的计算研究，表面活性剂诱导的病毒活性抑制，以及合成病毒粒子型药物载体纳米粒子通过细胞膜和其他生理界面的粘附和易位，产生跨学科的变革性影响。拟议的研究将支持多样性，培养研究生和本科生，并生产复杂生物纳米级系统建模模块。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。