Structural Ramifications of Spike Protein D614G Mutation in SARS-CoV-2
Structural Ramifications of Spike Protein D614G Mutation in SARS-CoV-2
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DOI：
10.1101/2022.01.24.477651
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发表时间：
2022-01
期刊：
影响因子：
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通讯作者：
H. Dokainish;Y. Sugita
中科院分区：
文献类型：
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作者：
H. Dokainish;Y. Sugita
在位置614处从天冬氨酸到甘氨酸的单一突变主导了严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的所有循环变体。D 614 G突变诱导刺突（S）蛋白的结构变化，从而增强病毒的感染性。在这里，我们使用分子动力学模拟来剖析突变和630环硬化对野生型结构的影响。引入具有有序630环的突变诱导朝向S-G614 Cryo-EM结构的结构变化。一个有序的630环削弱了稳定的相互作用的阴离子D 614，表明其在野生型的障碍。该突变变构地改变受体结合结构域（RBD），形成不对称的和移动的向下构象，其促进向上转变。突变后D614_K854盐桥的丢失通常稳定S蛋白原聚体，包括介导膜融合的融合肽近端区域。了解D 614 G的分子基础至关重要，因为它在所有相关变体中占主导地位，包括Delta和Omicron。
A single mutation from aspartate to glycine at position 614 has dominated all circulating variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). D614G mutation induces structural changes in the Spike (S) protein that strengthen the virus infectivity. Here, we use molecular dynamics simulations to dissect the effects of mutation and 630-loop rigidification on wild-type structure. The introduction of mutation with ordered 630-loop induces structural changes toward S-G614 Cryo-EM structure. An ordered 630-loop weakens the stabilizing interactions of the anionic D614, suggesting its disorder in wild-type. The mutation allosterically alters the receptor binding domain (RBD) forming an asymmetric and mobile Down conformation, which facilitate Up transition. The loss of D614_K854 salt-bridge upon mutation, generally stabilize S-protein protomer, including the fusion peptide proximal region that mediates membrane fusion. Understanding of the molecular basis of D614G is crucial as it dominates in all variants of concern including Delta and Omicron.