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

这个新冠肺炎探索性研究早期概念拨款(AGERGE)项目将研究导致这种疾病的SARS-CoV-2病毒如何附着在细胞上，以及当受到机械力时它可能如何分离。病毒通过其刺突蛋白附着在细胞上，人们认为这种蛋白质具有称为铰链的灵活区域，允许它改变形状以调节其附着。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铰链运动，从而影响病毒与细胞的结合。了解尖峰蛋白在病毒附着期间如何改变其形状，以及它如何分离，例如在咳嗽和打喷嚏期间，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，并提供找到治疗该疾病所需的基本见解。这项研究计划旨在实施一种新的计算策略，以了解Spike蛋白的铰链运动如何控制病毒附着。这种方法将把分子模拟与网络重建和群落检测方法结合起来，这些方法是蛋白质研究中的新方法。它的目的是准确识别蛋白质的软和硬区域，精确定位铰链运动，并研究机械力如何影响受体结合区域的可及性和结合强度。这将提供急需的物理洞察，了解SARS-CoV-2如何结合和感染细胞，当受到压力时它可能如何移开，以及抗体可以针对哪些顺应性区域来防止附着。推断网络特性的统计严谨技术将有助于正确识别控制病毒附着的区域。作为推广工作的一部分，将制作和传播关于尖峰蛋白动态和病毒附着的基于物理学的动画和视频。为从模拟中推断网络和铰链运动而开发的统计方法、代码和软件将与研究社区共享。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.