EAGER: Investigating the Hinge Mechanics of the Spike Protein to Understand the Coronavirus Infection Mechanism

这项COVID-19探索性研究早期概念资助（EAGER）项目将研究导致该疾病的SARS-CoV-2病毒如何附着在细胞上，以及在受到机械力时如何分离。这种病毒通过它的刺突蛋白附着在细胞上，人们相信这种蛋白质有一个叫做铰链的灵活区域，可以改变它的形状来调节它的附着。该项目将建立一种涉及分子模拟和数据科学方法的方法来可靠地识别这些铰链。这些分析旨在解释机械力和化学因素如何影响影响病毒与细胞结合的铰链运动。了解刺突蛋白在病毒附着过程中如何改变形状，以及它如何分离，例如在咳嗽和打喷嚏时，对于准确描述病毒如何进入细胞以及我们如何预防感染至关重要。这些发现将促进对这种新型冠状病毒的科学理解，并为找到治愈这种疾病所需的基本见解。本研究计划旨在实施一种新的计算策略，以了解刺突蛋白的铰链运动如何控制病毒附着。该方法将分子模拟与网络重建和社区检测方法相结合，这是蛋白质研究的新方法。它将旨在准确识别蛋白质的软和硬区域，查明铰链运动，并检查机械力如何影响受体结合域的可及性和结合强度。这将提供急需的物理见解，了解SARS-CoV-2如何结合和感染细胞，在受到外力时如何脱落，以及抗体可以靶向哪些顺应区域以防止附着。用于推断网络特性的统计严谨技术将有助于正确识别调节病毒附着的区域。作为推广工作的一部分，将制作和传播关于刺突蛋白动力学和病毒附着的基于物理的动画和视频。从模拟中推断网络和铰链运动的统计方法、代码和软件将与研究界共享。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 COVID-19 EArly-concept Grant for Exploratory Research (EAGER) project will investigate how SARS-CoV-2, virus causing the disease, attaches to cells, and how it may detach when subject to mechanical force. The virus attaches to cells through its spike protein, and it is believed that this protein has flexible regions called hinges that allow it to change its shape to regulate its attachment. This project will establish a method involving molecular simulations and data science methods to reliably identify these hinges. These analyses will aim to explain how mechanical forces and chemical factors influence hinge motions that influence the binding of the virus to cells. Understanding how the spike protein changes its shape during viral attachment, and how it may detach, e.g. during coughing and sneezing is critical for accurately describing how the virus enters cells, and how we can prevent infection. These findings will advance scientific understanding about this novel coronavirus and provide fundamental insights needed to find a cure for the disease. This research program will aim to implement a novel computational strategy to understand how hinge motions of the spike protein govern viral attachment. This method will combine molecular simulations with network reconstruction and community detection methods that are new to the study of proteins. It will aim to accurately identify soft and stiff regions of the protein, pinpoint hinge motions, and examine how mechanical forces impact receptor binding domain accessibility and binding strength. This will provide critically needed physical insights into how SARS-CoV-2 binds and infects cells, how it may dislodge when subject to force, and which compliant regions antibodies could target to prevent attachment. Statistically rigorous techniques for inferring network properties will help to correctly identify the regions that regulate viral attachment. As part of outreach efforts, physics-based animations and videos on the spike protein dynamics and viral attachment will be created and disseminated. Statistical methods, codes and software developed to infer networks and hinge motions from simulations will be shared with the research community.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.