RAPID: Computational studies of the structural dynamics, function and inhibition of the SARS-CoV-2 coronavirus spike protein

NSF快速反应研究（Rapid）项目由分子和细胞生物科学部分子生物物理项目资助，旨在通过计算机模拟局部受体/抗原结合和全局融合时冠状病毒膜表面尖峰(S)糖蛋白的动态转变，从而彻底表征冠状病毒膜表面尖峰(S)糖蛋白的动态转变。刺突蛋白与细胞表面的受体结合，并经历长时间、大规模的构象转变，从而引发融合。该项目将强调在增强采样模拟中部署最新进展的作用，以获得与实验时间尺度有效联系的热平均值和动力学平均值。从该项目中吸取的经验教训不仅将提高对SARS-CoV-2刺突蛋白结构和动力学的理解，而且将加深对病毒的分子生物物理学理解。除了直接的科学见解外，该项目还将影响研究生，本科生和中学生的教育，为大型研究社区提供信息，并通过外展活动吸引更广泛的公众。2019年新型冠状病毒被确定为武汉报告的肺炎病理的原因，迅速传播并成为全球大流行。该项目将采用基于严格统计力学的新型计算技术来了解刺突蛋白功能的动力学作用，刺突蛋白是关键的大分子成分，其结构重排负责抗体中和和进入宿主细胞进行感染。在最近发布的优先级建议中，世界卫生组织强调需要针对这种刺突蛋白的抗原。该项目将有助于解释生化测量的中和敏感性，受体反应性和免疫反应的变化，由于广泛的感染。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。

This NSF Rapid response Research (RAPID) project funded by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences will support a project that is aimed to thoroughly characterize the dynamical transitions the coronavirus membrane-surface spike (S) glycoprotein by computer simulations both locally upon receptor/antigen binding and globally upon fusion. The spike protein binds a receptor on the surface of the cell and undergoes a long-time, large-scale conformational transition that triggers fusion. This project will emphasize the role of deploying recent advances in enhanced sampling simulations to obtaining thermal and kinetic averages that make valid connection to the timescales of the experiments. Lessons learned from this project will not only improve the understanding of the structure and dynamics of the SARS-CoV-2 spike protein but will deepen the molecular biophysics understanding of viruses in general. In addition to direct scientific insights, the project will impact the education of graduate, undergraduate, and middle-school students, inform a large research community, and engage the broader public through outreach activities.The 2019 novel coronavirus, identified as the cause for the pneumonia pathology reported in Wuhan, spread quickly and became a global pandemic. The project will employ novel computational techniques grounded in rigorous statistical mechanics to understand the role of the dynamics for the function of the spike protein, the key macromolecular component whose structural rearrangements are responsible for antibody neutralization and entry to the host cell for infection. In its recently released prioritization recommendation, the World Health Organization stressed the need for antigens to target this spike protein. This project will help in the interpretation of biochemical measurements on neutralization sensitivity, receptor reactivity, and immunity response changes due to widespread infection.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.