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

芝加哥大学的Gregory Voth得到了这个RAPID奖的支持，以开发和部署整个SARS-CoV-2病毒的多尺度模型，该病毒导致2019年新型冠状病毒传染病（COVID-19）。 这样的多尺度模型，在原子和粗颗粒水平，大大有助于我们了解这种病毒如何复制。 COVID-19病毒过程的分子模拟有助于识别病毒生命周期中可能的弱点。 这项研究的重点是冠状病毒过程的动力学，包括病毒发挥功能所需的构象转变。该项目有三个主要焦点：1）病毒生命周期所必需的单个病毒蛋白质的全原子模拟; 2）整体理解整个病毒粒子的粗粒模型（宿主细胞外的病毒）及其大规模过程，如病毒体与宿主细胞的融合;以及3）基于机器学习的方法来连接全原子模型和粗粒度模型并进一步改进其精度。 作为一个更大的、致力于COVID-19的国际社区的一部分，所有数据、模型和分析代码一旦开发出来，将立即公开，包括通过NSF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。该RAPID项目的研究是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）使用全原子分子动力学模拟来表征所涉及的病毒蛋白质的动力学行为，并理解其功能所必需的构象转变：（2）使用粗粒度模拟方法开发和模拟完整的SARS-CoV-2病毒粒子;以及（3）开发基于机器学习的方法，该方法系统地链接原子级和粗粒度仿真尺度，并且促进生成甚至更准确和描述性的粗粒度模型。这项研究的重点是几个生物分子系统，迫切需要了解和表征SARS-CoV-2病毒的传播和繁殖，包括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，特别是在接下来的几个月里，结构数据和生化信息将被公布。粗粒度模拟将侧重于开发整个SARS-CoV-2病毒体及其大规模过程（如病毒体与宿主细胞融合）的整体模型的迫切需要。该奖项反映了NSF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.