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

被引:457
作者
Casalino, Lorenzo [1 ]
Gaieb, Zied [1 ]
Goldsmith, Jory A. [2 ]
Hjorth, Christy K. [2 ]
Dommer, Abigail C. [1 ]
Harbison, Aoife M. [3 ,4 ]
Fogarty, Carl A. [3 ,4 ]
Barros, Emilia P. [1 ]
Taylor, Bryn C. [1 ,5 ]
McLellan, Jason S. [2 ]
Fadda, Elisa [3 ,4 ]
Amaro, Rommie E. [1 ,5 ]
机构
[1] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA
[2] Univ Texas Austin, Dept Mol Biosci, Austin, TX 78712 USA
[3] Maynooth Univ, Dept Chem, Dublin, Ireland
[4] Maynooth Univ, Hamilton Inst, Dublin, Ireland
[5] Univ Calif San Diego, Biomed Sci Grad Program, La Jolla, CA 92093 USA
关键词
MOLECULAR-DYNAMICS; DC-SIGN; FORCE-FIELD; CORONAVIRUS; ENTRY; NEUTRALIZATION; BILAYERS; CHAIN; GUI;
D O I
10.1021/acscentsci.0c01056
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 28,000,000 infections and 900,000 deaths worldwide to date. Antibody development efforts mainly revolve around the extensively glycosylated SARS-CoV-2 spike (S) protein, which mediates host cell entry by binding to the angiotensin-converting enzyme 2 (ACE2). Similar to many other viral fusion proteins, the SARS-CoV-2 spike utilizes a glycan shield to thwart the host immune response. Here, we built a full-length model of the glycosylated SARS-CoV-2 S protein, both in the open and dosed states, augmenting the available structural and biological data. Multiple microsecond-long, all-atom molecular dynamics simulations were used to provide an atomistic perspective on the roles of glycans and on the protein structure and dynamics. We reveal an essential structural role of N-glycans at sites N165 and N234 in modulating the conformational dynamics of the spike's receptor binding domain (RBD), which is responsible for ACE2 recognition. This finding is corroborated by biolayer interferometry experiments, which show that deletion of these glycans through N165A and N234A mutations significantly reduces binding to ACE2 as a result of the RBD conformational shift toward the "down" state. Additionally, end-to-end accessibility analyses outline a complete overview of the vulnerabilities of the glycan shield of the SARS-CoV-2 S protein, which may be exploited in the therapeutic efforts targeting this molecular machine. Overall, this work presents hitherto unseen functional and structural insights into the SARS-CoV-2 S protein and its glycan coat, providing a strategy to control the conformational plasticity of the RBD that could be harnessed for vaccine development.
引用
收藏
页码:1722 / 1734
页数:13
相关论文
共 73 条
[1]   Human Influenza A Virus Hemagglutinin Glycan Evolution Follows a Temporal Pattern to a Glycan Limit [J].
Altman, Meghan O. ;
Angel, Matthew ;
Kosik, Ivan ;
Trovao, Nidia S. ;
Zost, Seth J. ;
Gibbs, James S. ;
Casalino, Lorenzo ;
Amaro, Rommie E. ;
Hensley, Scott E. ;
Nelson, Martha I. ;
Yewdell, Jonathan W. .
MBIO, 2019, 10 (02)
[2]   A Community Letter Regarding Sharing Biomolecular Simulation Data for COVID-19 [J].
Amaro, Rommie E. ;
Mulholland, Adrian J. .
JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2020, 60 (06) :2653-2656
[3]  
[Anonymous], 2020, Data, DOI DOI 10.1038/S41597-020-0479-6
[4]   The three lives of viral fusion peptides [J].
Apellaniz, Beatriz ;
Huarte, Nerea ;
Largo, Eneko ;
Nieva, Jose L. .
CHEMISTRY AND PHYSICS OF LIPIDS, 2014, 181 :40-55
[5]   Structural principles controlling HIV envelope glycosylation [J].
Behrens, Anna-Janina ;
Crispin, Max .
CURRENT OPINION IN STRUCTURAL BIOLOGY, 2017, 44 :125-133
[6]   Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites [J].
Belouzard, Sandrine ;
Chu, Victor C. ;
Whittaker, Gary R. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (14) :5871-5876
[7]   Detailed molecular dynamics simulations of model biological membranes containing cholesterol [J].
Berkowitz, Max L. .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 2009, 1788 (01) :86-96
[8]   The Glycan Shield of HIV Is Predominantly Oligomannose Independently of Production System or Viral Clade [J].
Bonomelli, Camille ;
Doores, Katie J. ;
Dunlop, D. Cameron ;
Thaney, Victoria ;
Dwek, Raymond A. ;
Burton, Dennis R. ;
Crispin, Max ;
Scanlan, Christopher N. .
PLOS ONE, 2011, 6 (08)
[9]   Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability [J].
Brouwer, Philip J. M. ;
Caniels, Tom G. ;
van der Straten, Karlijn ;
Snitselaar, Jonne L. ;
Aldon, Yoann ;
Bangaru, Sandhya ;
Torres, Jonathan L. ;
Okba, Nisreen M. A. ;
Claireaux, Mathieu ;
Kerster, Gius ;
Bentlage, Arthur E. H. ;
van Haaren, Marlies M. ;
Guerra, Denise ;
Burger, Judith A. ;
Schermer, Edith E. ;
Verheul, Kirsten D. ;
van der Velde, Niels ;
van der Kooi, Alex ;
van Schooten, Jelle ;
van Breemen, Marielle J. ;
Bijl, Tom P. L. ;
Sliepen, Kwinten ;
Aartse, Aafke ;
Derking, Ronald ;
Bontjer, Ilja ;
Kootstra, Neeltje A. ;
Wiersinga, W. Joost ;
Vidarsson, Gestur ;
Haagmans, Bart L. ;
Ward, Andrew B. ;
de Bree, Godelieve J. ;
Sanders, Rogier W. ;
van Gils, Marit J. .
SCIENCE, 2020, 369 (6504) :643-+
[10]   Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan [J].
Chan, Jasper Fuk-Woo ;
Kok, Kin-Hang ;
Zhu, Zheng ;
Chu, Hin ;
To, Kelvin Kai-Wang ;
Yuan, Shuofeng ;
Yuen, Kwok-Yung .
EMERGING MICROBES & INFECTIONS, 2020, 9 (01) :221-236