RAPID: Understanding the Effects of Glycosylation on Spike Vulnerabilities and the Host Range of SARS-CoV-2

RAPID：了解糖基化对 SARS-CoV-2 尖峰脆弱性和宿主范围的影响

• 批准号: 2032054
• 负责人: Rommie Amaro
• 金额: $ 19.99万
• 依托单位: University of California-San Diego
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2032054&HistoricalAwards=false
• 关键词: RAPID; Understanding; Effects; Glycosylation; Spike

The COVID-19 pandemic is caused by the SARS-CoV-2 virus, a virus whose structure has not been fully characterized. The spike protein of the virus is believed to play a key role in infection. In this work computer simulations will be used to understand the role of sugar molecules that normally are present on the outside of host cells on the binding to host cells and the infectivity of the virus. Simulations will examine host cell membranes from species that include humans, cats, ferrets and other non-human primates in order to better understand the differences between virus transmission in different species. These simulations will provide information that is not currently accessible through experiment. The simulations and data sharing capabilities developed in this work will improve responsiveness against future pandemics. Additionally, the project will provide a training for two postdoctoral fellows. This research will use MD (molecular dynamics) computational methodology together with experimental data, to build and simulate biologically realistic conditions for the SARS-CoV-2 virus spike protein, alone, and also in complex with various forms of the ACE2 receptor and host cell membrane components. The aim is to determine areas of spike protein vulnerabilities as well as understand the effects of glycosylation on the structure and function of the SARS-CoV-2 infection machinery. The simulations will include ACE2 receptors in cats, ferrets, and other nonhuman primates to understand the molecular underpinnings of virus host range and transmissibility. The proposed research will provide a more complete understanding of the SARS-CoV-2 infection machinery and the molecular constituents with which it interacts at different host cells. This RAPID award is made by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.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.

COVID-19大流行是由SARS-CoV-2病毒引起的，这种病毒的结构尚未完全确定。病毒的刺突蛋白被认为在感染中起着关键作用。在这项工作中，计算机模拟将用于了解通常存在于宿主细胞外部的糖分子在与宿主细胞结合和病毒传染性中的作用。模拟将检查包括人类、猫、雪貂和其他非人类灵长类动物在内的物种的宿主细胞膜，以便更好地了解不同物种之间病毒传播的差异。这些模拟将提供目前无法通过实验获得的信息。在这项工作中开发的模拟和数据共享能力将提高对未来流行病的响应能力。此外，该项目还将为两名博士后提供培训。本研究将使用MD（分子动力学）计算方法结合实验数据，建立和模拟SARS-CoV-2病毒刺突蛋白单独以及与各种形式的ACE2受体和宿主细胞膜组分复合的生物学现实条件。目的是确定刺突蛋白的脆弱性区域，并了解糖基化对SARS-CoV-2感染机制的结构和功能的影响。模拟将包括猫、雪貂和其他非人灵长类动物的ACE2受体，以了解病毒宿主范围和传播性的分子基础。拟议的研究将更全面地了解SARS-CoV-2感染机制及其在不同宿主细胞中相互作用的分子成分。该RAPID奖由分子和细胞生物科学部分子生物物理学项目利用《冠状病毒援助、救济和经济安全（CARES）法案》的资金设立。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。

项目成果

Biomolecular Simulations in the Time of COVID19, and After.

• DOI: 10.1109/mcse.2020.3024155
• 发表时间: 2020-11
• 期刊: Computing in science & engineering
• 影响因子: 2.1
• 作者: Amaro RE;Mulholland AJ
• 通讯作者: Mulholland AJ

Beyond Shielding: The Roles of Glycans in the SARS-CoV-2 Spike Protein.

超越屏蔽：聚糖在SARS-COV-2尖峰蛋白中的作用。

• DOI: 10.1021/acscentsci.0c01056
• 发表时间: 2020-10-28
• 期刊: ACS central science
• 影响因子: 18.2
• 作者: Casalino L;Gaieb Z;Goldsmith JA;Hjorth CK;Dommer AC;Harbison AM;Fogarty CA;Barros EP;Taylor BC;McLellan JS;Fadda E;Amaro RE
• 通讯作者: Amaro RE

AI-driven multiscale simulations illuminate mechanisms of SARS-CoV-2 spike dynamics

• DOI: 10.1177/10943420211006452
• 发表时间: 2021-09
• 期刊: The International Journal of High Performance Computing Applications
• 作者: Casalino L;Dommer AC;Gaieb Z;Barros EP;Sztain T;Ahn SH;Trifan A;Brace A;Bogetti AT;Clyde A;Ma H;Lee H;Turilli M;Khalid S;Chong LT;Simmerling C;Hardy DJ;Maia JD;Phillips JC;Kurth T;Stern AC;Huang L;McCalpin JD;Tatineni M;Gibbs T;Stone JE;Jha S;Ramanathan A;Amaro RE
• 通讯作者: Amaro RE