Atomistic simulation reveals structural mechanisms underlyingD614Gspike glycoprotein-enhanced fitness inSARS-COV-2
Atomistic simulation reveals structural mechanisms underlyingD614Gspike glycoprotein-enhanced fitness inSARS-COV-2
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DOI：
10.1002/jcc.26383
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发表时间：
2020-07-21
影响因子：
3
通讯作者：
Okaiyeto, Kunle
中科院分区：
文献类型：
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作者：
Omotuyi, I. Olaposi;Nash, Oyekanmi;Okaiyeto, Kunle
在迅速传播的严重急性呼吸综合征冠状病毒2型中，D614G刺激性糖蛋白突变与新冠肺炎新病例的适应性增强和更高的传播率有关，但其潜在机制尚不清楚。在这里，使用原子模拟，描述了一种合理的机制。在G614 SGP中，但不是野生型，在65 ns内D(G)614-T859 Cα距离的增加被解释为S1/S2原始体的解离。总体而言，G614突变体优先选择ACE2结合构象、融合后核心构象、开放状态和次优抗体结合构象，而不是野生型。此外，在野生型中，三条SGP链中只有一条在残基614和受体结合域(RBD)之间具有最佳的通信路径，而在G614突变体中，三条链中的两条直接通信。这些数据为D614G Sgp突变体更适合于受体结合、细胞侵袭和抗体相互作用减少提供了证据，从而为D614G SARS-COV-2突变体增强适合性和更高的传播性提供了框架。
D614G spike glycoprotein (sgp) mutation in rapidly spreading severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) is associated with enhanced fitness and higher transmissibility in new cases of COVID-19 but the underlying mechanism is unknown. Here, using atomistic simulation, a plausible mechanism has been delineated. In G614 sgp but not wild type, increased D(G)614-T859 C alpha-distance within 65 ns is interpreted as S1/S2 protomer dissociation. Overall, ACE2-binding, post-fusion core, open-state and sub-optimal antibody-binding conformations were preferentially sampled by the G614 mutant, but not wild type. Furthermore, in the wild type, only one of the three sgp chains has optimal communication route between residue 614 and the receptor-binding domain (RBD); whereas, two of the three chains communicated directly in G614 mutant. These data provide evidence that D614G sgp mutant is more available for receptor binding, cellular invasion and reduced antibody interaction; thus, providing framework for enhanced fitness and higher transmissibility in D614G SARS-COV-2 mutant.