Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core.
Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core.
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DOI：
10.1038/s41467-022-28654-5
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发表时间：
2022-02-22
影响因子：
16.6
通讯作者：
Voth GA
中科院分区：
文献类型：
--
作者：
Pak AJ;Yu A;Ke Z;Briggs JAG;Voth GA
出于基本原因和治疗原因，了解允许严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的刺突糖蛋白结合并进入细胞的分子事件非常重要。刺突蛋白由 S1 和 S2 结构域组成，分别识别血管紧张素转换酶 2 (ACE2) 受体并包含病毒融合机制。表面上，刺突三聚体与 ACE2 受体的结合促进了 S1 结构域的解离和融合机制的暴露，尽管这一过程的分子细节尚未观察到。我们报告了与冷冻电子断层扫描数据一致的自下而上的粗粒度 (CG) 模型的开发，以及使用 CG 分子动力学模拟来研究病毒结合和 S2 核心暴露。我们发现，刺突三聚体在病毒粒子-细胞界面上与多个 ACE2 二聚体协同结合，其方式不同于可溶性蛋白质之间的结合，从而逐渐诱导 S1 解离。我们还使用扰动的 CG 模型模拟可能的变异行为，发现 ACE2 诱导的 S1 解离主要对构象状态群体和 S1/S2 裂解的程度敏感，而不是对 ACE2 结合亲和力敏感。这些模拟揭示了刺突三聚体和 ACE2 二聚体之间重要的协同相互作用，为病毒进行膜融合和进入做好准备。模拟揭示了 SARS-CoV-2 刺突三聚体和 ACE2 受体之间的协同相互作用，导致刺突的协同结合和脱落，并进一步表明 RBD 开放或 S1/S2 裂解效率的增加可促进变异功效。
The molecular events that permit the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind and enter cells are important to understand for both fundamental and therapeutic reasons. Spike proteins consist of S1 and S2 domains, which recognize angiotensin-converting enzyme 2 (ACE2) receptors and contain the viral fusion machinery, respectively. Ostensibly, the binding of spike trimers to ACE2 receptors promotes dissociation of the S1 domains and exposure of the fusion machinery, although the molecular details of this process have yet to be observed. We report the development of bottom-up coarse-grained (CG) models consistent with cryo-electron tomography data, and the use of CG molecular dynamics simulations to investigate viral binding and S2 core exposure. We show that spike trimers cooperatively bind to multiple ACE2 dimers at virion-cell interfaces in a manner distinct from binding between soluble proteins, which processively induces S1 dissociation. We also simulate possible variant behavior using perturbed CG models, and find that ACE2-induced S1 dissociation is primarily sensitive to conformational state populations and the extent of S1/S2 cleavage, rather than ACE2 binding affinity. These simulations reveal an important concerted interaction between spike trimers and ACE2 dimers that primes the virus for membrane fusion and entry. Simulations reveal concerted interactions between the SARS-CoV-2 spike trimers and ACE2 receptors that result in cooperative spike binding and shedding, and further suggest that variant efficacy is promoted by increased RBD opening or S1/S2 cleavage efficiency.
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影响因子：
6.7
作者：
Laporte M;Raeymaekers V;Van Berwaer R;Vandeput J;Marchand-Casas I;Thibaut HJ;Van Looveren D;Martens K;Hoffmann M;Maes P;Pöhlmann S;Naesens L;Stevaert A
通讯作者：
Stevaert A
SARS-COV-2血统的估计可传播和影响B.1.1.7在英国。
DOI：
10.1126/science.abg3055
发表时间：
2021-04-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Davies NG;Abbott S;Barnard RC;Jarvis CI;Kucharski AJ;Munday JD;Pearson CAB;Russell TW;Tully DC;Washburne AD;Wenseleers T;Gimma A;Waites W;Wong KLM;van Zandvoort K;Silverman JD;CMMID COVID-19 Working Group;COVID-19 Genomics UK (COG-UK) Consortium;Diaz-Ordaz K;Keogh R;Eggo RM;Funk S;Jit M;Atkins KE;Edmunds WJ
通讯作者：
Edmunds WJ
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
DOI：
10.1177/10943420211006452
发表时间：
2021-09
期刊：
The International Journal of High Performance Computing Applications
影响因子：
--
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
影响因子：
5.5
作者：
Li, Lin;Li, Chuan;Zhang, Zhe;Alexov, Emil
通讯作者：
Alexov, Emil