Shi Chengcheng, Jiao Yanqi, Yang Chao, Sun Yao
School of Science, Harbin Institute of Technology (Shenzhen) Shenzhen 518055 China
State Key Lab of Urban Water Resource and Environment, School of Science, Harbin Institute of Technology (Shenzhen) Shenzhen 518055 China
RSC Adv. 2023 Mar 28;13(15):9800-9810. doi: 10.1039/d3ra00198a. eCollection 2023 Mar 27.
SARS-CoV-2 has continuously evolved as changes in the genetic code occur during replication of the genome, with some of the mutations leading to higher transmission among human beings. The spike aspartic acid-614 to glycine (D614G) substitution in the spike represents a "more transmissible form of SARS-CoV-2" and occurs in all SARS-CoV-2 mutants. However, the underlying mechanism of the D614G substitution in virus infectivity has remained unclear. In this paper, we adopt molecular simulations to study the contact processes of the D614G mutant and wild-type (WT) spikes with hACE2. The interaction areas with hACE2 for the two spikes are completely different by visualizing the whole binding processes. The D614G mutant spike moves towards the hACE2 faster than the WT spike. We have also found that the receptor-binding domain (RBD) and N-terminal domain (NTD) of the D614G mutant extend more outwards than those of the WT spike. By analyzing the distances between the spikes and hACE2, the changes of number of hydrogen bonds and interaction energy, we suggest that the increased infectivity of the D614G mutant is not possibly related to the binding strength, but to the binding velocity and conformational change of the mutant spike. This work reveals the impact of D614G substitution on the infectivity of the SARS-CoV-2, and hopefully could provide a rational explanation of interaction mechanisms for all the SARS-CoV-2 mutants.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）在基因组复制过程中，随着遗传密码的变化不断进化，其中一些突变导致其在人群中的传播能力增强。刺突蛋白中天门冬氨酸614位点突变为甘氨酸（D614G）的替换代表了一种“传播性更强的SARS-CoV-2形式”，且存在于所有SARS-CoV-2突变体中。然而，D614G替换对病毒感染性的潜在机制仍不清楚。在本文中，我们采用分子模拟方法研究D614G突变体和野生型（WT）刺突蛋白与人类血管紧张素转换酶2（hACE2）的接触过程。通过可视化整个结合过程，发现两种刺突蛋白与hACE2的相互作用区域完全不同。D614G突变体刺突蛋白比野生型刺突蛋白更快地向hACE2移动。我们还发现，D614G突变体的受体结合域（RBD）和N端结构域（NTD）比野生型刺突蛋白向外延伸得更多。通过分析刺突蛋白与hACE2之间的距离、氢键数量的变化以及相互作用能，我们认为D614G突变体感染性增加可能与结合强度无关，而是与突变体刺突蛋白的结合速度和构象变化有关。这项工作揭示了D614G替换对SARS-CoV-2感染性的影响，有望为所有SARS-CoV-2突变体的相互作用机制提供合理的解释。
