SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome.
SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome.
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DOI：
10.1038/s41557-021-00707-0
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发表时间：
2021-07
期刊：
影响因子：
21.8
通讯作者：
Bowman GR
中科院分区：
文献类型：
--
作者：
Zimmerman MI;Porter JR;Ward MD;Singh S;Vithani N;Meller A;Mallimadugula UL;Kuhn CE;Borowsky JH;Wiewiora RP;Hurley MFD;Harbison AM;Fogarty CA;Coffland JE;Fadda E;Voelz VA;Chodera JD;Bowman GR
SARS-CoV-2具有启动感染、免疫逃避/抑制和复制的复杂机制，这些机制取决于其组成蛋白的结构和动力学。许多蛋白质结构已经被解决，但对它们的相关构象变化知之甚少。为了应对这一挑战，100多万名公民科学家通过Folding@home分布式计算项目联合起来，创造了第一台艾级计算机，并模拟了前所未有的0.1秒的病毒蛋白质组。我们的模拟捕捉到了apo Spike复合体戏剧性的打开，远远超出了实验中看到的，这解释并成功地预测了“神秘”表位的存在。不同的Spike同系物调节开放结构和关闭结构的可能性，平衡受体结合和免疫逃避。我们还观察到整个蛋白质组的戏剧性构象变化，揭示了50多个“神秘”的口袋，这些口袋扩大了抗病毒药物设计的靶向选择。所有数据和模型都可以在网上免费获得，提供了一份量化的结构图集。
SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression, and replication, which depend on the structure and dynamics of its constituent proteins. Many protein structures have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through the Folding@home distributed computing project to create the first exascale computer and simulate an unprecedented 0.1 seconds of the viral proteome. Our simulations capture dramatic opening of the apo Spike complex, far beyond that seen experimentally, which explains and successfully predicts the existence of ‘cryptic’ epitopes. Different Spike homologues modulate the probabilities of open versus closed structures, balancing receptor binding and immune evasion. We also observe dramatic conformational changes across the proteome, which reveal over 50 ‘cryptic’ pockets that expand targeting options for the design of antivirals. All data and models are freely available online, providing a quantitative structural atlas.
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