Structure, Dynamics, Receptor Binding, and Antibody Binding of the Fully Glycosylated Full-Length SARS-CoV-2 Spike Protein in a Viral Membrane.
Structure, Dynamics, Receptor Binding, and Antibody Binding of the Fully Glycosylated Full-Length SARS-CoV-2 Spike Protein in a Viral Membrane.
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DOI：
10.1021/acs.jctc.0c01144
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发表时间：
2021-04-13
影响因子：
5.5
通讯作者：
Im W
中科院分区：
文献类型：
--
作者：
Choi YK;Cao Y;Frank M;Woo H;Park SJ;Yeom MS;Croll TI;Seok C;Im W
严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）的刺突蛋白（S）通过与血管紧张素转换酶2（ACE 2）结合介导宿主细胞进入，被认为是药物和疫苗开发的主要靶点。我们先前在病毒膜中建立了完全糖基化的全长SARS-CoV-2 S蛋白模型，包括受体结合结构域（RBD）的开放和闭合构象以及茎区的不同模板。在这项工作中，多个μ s长的全原子分子动力学模拟进行了更深入的了解S蛋白和聚糖功能的结构和动力学。我们的模拟结果表明，高度灵活的柄是由两个独立的关节和最可能的S蛋白的方向是有能力的ACE 2结合。我们确定了多个聚糖稳定的开放和/或封闭状态的RBD和证明，抗体表位的暴露可以捕获详细的抗体-聚糖冲突分析，而不是常用的可及表面积分析，往往高估的影响聚糖屏蔽和忽视可能的详细的聚糖和抗体之间的相互作用。总的来说，我们的观察提供了结构和动态的见解SARS-CoV-2 S蛋白和潜在的指导设计有效的抗病毒治疗。
The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates host cell entry by binding to angiotensin-converting enzyme 2 (ACE2) and is considered the major target for drug and vaccine development. We previously built fully glycosylated full-length SARS-CoV-2 S protein models in a viral membrane including both open and closed conformations of the receptor-binding domain (RBD) and different templates for the stalk region. In this work, multiple μs-long all-atom molecular dynamics simulations were performed to provide deeper insights into the structure and dynamics of S protein and glycan functions. Our simulations reveal that the highly flexible stalk is composed of two independent joints and most probable S protein orientations are competent for ACE2 binding. We identify multiple glycans stabilizing the open and/or closed states of the RBD and demonstrate that the exposure of antibody epitopes can be captured by detailed antibody–glycan clash analysis instead of commonly used accessible surface area analysis that tends to overestimate the impact of glycan shielding and neglect possible detailed interactions between glycan and antibodies. Overall, our observations offer structural and dynamic insights into the SARS-CoV-2 S protein and potentialize for guiding the design of effective antiviral therapeutics.
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影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
超越屏蔽：聚糖在SARS-COV-2尖峰蛋白中的作用。
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
影响因子：
3.7
作者：
Jo S;Kim T;Im W
通讯作者：
Im W
影响因子：
64.8
作者：
Ke, Zunlong;Oton, Joaquin;Briggs, John A. G.
通讯作者：
Briggs, John A. G.
影响因子：
2.9
作者：
HOOVER, WG
通讯作者：
HOOVER, WG