RAPID: Data-driven Multiscale Integrative Model of the Coronavirus Virion

芝加哥大学的格雷戈里·沃斯（Gregory Voth）得到了该RAPID奖的支持，开发和部署了整个SARS-CoV-2病毒的多尺度模型，该病毒是导致2019年新型冠状病毒传染病（COVID-19）的病毒。这种原子级和粗粒级的多尺度模型极大地有助于我们了解这种病毒是如何复制的。对COVID-19病毒过程的分子模拟有助于确定病毒生命周期中可能存在的弱点。这项研究的重点是冠状病毒过程的动力学，包括病毒功能所需的构象转变。该项目有三个主要重点：1)对病毒生命周期至关重要的单个病毒蛋白质的全原子模拟；2)用粗粒度模型来全面理解整个病毒粒子（宿主细胞外的病毒）及其大规模过程，如病毒粒子与宿主细胞的融合；3)基于机器学习的方法，将全原子模型和粗粒模型联系起来，进一步提高其准确性。作为致力于COVID-19的更大国际社区的一部分，所有数据、模型和分析代码一经开发就将公开提供，包括通过美国国家科学基金会资助的分子科学软件研究所（MolSSI）。病毒结构和动力学的完整多尺度图像将用于确定药物开发和其他治疗策略的潜在靶点。本RAPID项目的研究旨在开发和应用多尺度计算机模拟方法，以表征SARS-CoV-2复制中大规模病毒过程的关键要素。为了实现这一目标，有三个主要目标：(1)利用全原子分子动力学模拟来表征必需病毒蛋白的动力学行为，并了解其功能所需的构象转变；(2)采用粗粒度模拟方法建立完整的SARS-CoV-2病毒粒子模型；(3)开发基于机器学习的方法，系统地将原子级和粗粒度模拟尺度联系起来，并促进生成更准确和更具描述性的粗粒度模型。本研究重点关注了介导病毒颗粒进入宿主细胞的刺突蛋白、宿主细胞受体、结合刺突蛋白的血管紧张素转换酶2、催化病毒过程的冠状病毒蛋白酶以及其他病毒蛋白组分等急需的生物分子系统，以了解和表征SARS-CoV-2病毒的传播和繁殖。特别是在未来几个月，结构数据和生化信息将会公布。粗粒度模拟将侧重于迫切需要建立整个SARS-CoV-2病毒粒子及其大规模过程（如病毒粒子与宿主细胞融合）的整体模型。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。

Gregory Voth of the University of Chicago is supported by this RAPID award to develop and deploy multiscale models of the entire SARS-CoV-2 virus, the virus that causes the novel coronavirus infectious disease 2019 (COVID-19). Such multiscale models, at both the atomistic and coarse grain levels, contribute greatly to our understanding of how this virus replicates. Molecular simulations of viral processes in COVID-19 are useful to identify possible weaknesses in the viral life cycle. This research focuses on the dynamics of coronavirus processes, including the conformational transitions that are required for the virus to function. The project has three main foci: 1) all-atom simulations of individual viral proteins that are essential to the viral life cycle; 2) a coarse-grain models to a holistic understanding of entire virion (the virus outside the host cell) and its large scale processes, such as fusion of virions with host cells; and 3) machine-learning-based approaches to link the all-atom and coarse grain models and further refine their accuracy. As part of a larger, international community working on COVID-19, all data, models and analysis code will be made publicly available as soon as they are developed, including through the NSF-funded Molecular Science Software Institute (MolSSI). The complete multiscale picture of virus structure and dynamics will be used to identify potential target sites for drug development and other therapeutic strategies.The research in this RAPID project is for the development and application of multiscale computer simulation methods to characterize key elements of large-scale viral processes in SARS-CoV-2 replication. To achieve this goal there are three main objectives: (1) to characterize the dynamical behavior of essential viral proteins involved using all-atom molecular dynamics simulations and understand the conformational transitions necessary for their function; (2) to develop and model the complete SARS-CoV-2 virion using coarse-grained simulation methods; and (3) to develop machine learning based approaches that systematically link atomic-level and coarse-grained simulation scales, and facilitate the generation of even more accurate and descriptive coarse-grained models. This research focuses on several biomolecular systems that are urgently needed to understand and characterize the transmission and propagation of the SARS-CoV-2 virus, including the spike protein that mediates entry of the viral particles into host cells, the host cell receptor, angiotensin-converting-enzyme 2, which binds the spike protein, coronavirus protease which catalyzes viral processes, and other viral protein components, especially as structural data and biochemical information are released in the next few months. Coarse-grained simulations will focus on the urgent need to develop a holistic model of the entire SARS-CoV-2 virion as well as its large-scale processes such as the fusion of virions with host cells.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.