Biomechanical characterization of SARS-CoV-2 spike RBD and human ACE2 protein-protein interaction.
Biomechanical characterization of SARS-CoV-2 spike RBD and human ACE2 protein-protein interaction.
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DOI：
10.1016/j.bpj.2021.02.007
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发表时间：
2021-03-16
影响因子：
3.4
通讯作者：
Zhang XF
中科院分区：
文献类型：
--
作者：
Cao W;Dong C;Kim S;Hou D;Tai W;Du L;Im W;Zhang XF
当前的COVID-19疫情对全球造成了毁灭性的影响。已知严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）（引起COVID-19的病毒）使用病毒表面刺突（S）蛋白的受体结合结构域（RBD）与许多人类细胞类型上表达的血管紧张素转换酶2（ACE 2）受体相互作用。RBD-ACE 2相互作用是介导SARS-CoV-2进入宿主细胞的关键步骤。最近的研究表明，ACE 2与SARS-CoV-2 S蛋白的相互作用具有比其与SARS-CoV-1的结构相同的S蛋白的结合更高的亲和力，SARS-CoV-1是导致2002-2004 SARS爆发的病毒。然而，这种结合亲和力差异背后的生物物理机制尚不清楚。本研究利用结合单分子力谱和转向分子动力学（SMD）模拟方法来量化SARS-CoV-2或SARS-CoV-1 RBD和ACE 2之间的特异性相互作用。根据加载速率的不同，SARS-CoV-2 RBD和ACE 2之间的解结合力范围为70 - 105 pN，比相似加载速率下SARS-CoV-1 RBD和ACE 2的解结合力高30-40%。SMD结果表明SARS-CoV-2 RBD与ACE 2的Asn 90上的N-连接聚糖相互作用。这种相互作用在SARS-CoV-1 RBD-ACE 2复合物中几乎不存在。在SMD模拟期间，额外的RBD-N-聚糖相互作用有助于更大的力和延长的相互作用寿命。我们的实验力谱研究证实了观察。去除ACE 2上的N-连接聚糖后，其与SARS-CoV-2 RBD的机械结合强度降低至与SARS-CoV-1 RBD-ACE 2相互作用相似的水平。总之，这项研究揭示了SARS-CoV-2和SARS-CoV-1之间ACE 2结合差异背后的机制，并可能有助于开发阻断SARS-CoV-2进入的新策略。
The current COVID-19 pandemic has led to a devastating impact across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (the virus causing COVID-19) is known to use the receptor-binding domain (RBD) at viral surface spike (S) protein to interact with the angiotensin-converting enzyme 2 (ACE2) receptor expressed on many human cell types. The RBD-ACE2 interaction is a crucial step to mediate the host cell entry of SARS-CoV-2. Recent studies indicate that the ACE2 interaction with the SARS-CoV-2 S protein has a higher affinity than its binding with the structurally identical S protein of SARS-CoV-1, the virus causing the 2002–2004 SARS outbreak. However, the biophysical mechanism behind such binding affinity difference is unclear. This study utilizes combined single-molecule force spectroscopy and steered molecular dynamics (SMD) simulation approaches to quantify the specific interactions between SARS-CoV-2 or SARS-CoV-1 RBD and ACE2. Depending on the loading rates, the unbinding forces between SARS-CoV-2 RBD and ACE2 range from 70 to 105 pN and are 30–40% higher than those of SARS-CoV-1 RBD and ACE2 under similar loading rates. SMD results indicate that SARS-CoV-2 RBD interacts with the N-linked glycan on Asn90 of ACE2. This interaction is mostly absent in the SARS-CoV-1 RBD-ACE2 complex. During the SMD simulations, the extra RBD-N-glycan interaction contributes to a greater force and prolonged interaction lifetime. The observation is confirmed by our experimental force spectroscopy study. After removing N-linked glycans on ACE2, its mechanical binding strength with SARS-CoV-2 RBD decreases to a similar level of the SARS-CoV-1 RBD-ACE2 interaction. Together, the study uncovers the mechanism behind the difference in ACE2 binding between SARS-CoV-2 and SARS-CoV-1 and could help develop new strategies to block SARS-CoV-2 entry.
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DOI：
10.1007/978-1-4939-8591-3_29
发表时间：
2018-01-01
期刊：
NANOSCALE IMAGING: METHODS AND PROTOCOLS
影响因子：
--
作者：
Delguste, Martin;Koehler, Melanie;Alsteens, David
通讯作者：
Alsteens, David
影响因子：
3.4
作者：
Chesla, SE;Selvaraj, P;Zhu, C
通讯作者：
Zhu, C
影响因子：
8.6
作者：
Dion, M;Rydberg, H;Lundqvist, BI
通讯作者：
Lundqvist, BI
影响因子：
3.4
作者：
Evans, E;Ritchie, K
通讯作者：
Ritchie, K
影响因子：
1.6
作者：
HUTTER, JL;BECHHOEFER, J
通讯作者：
BECHHOEFER, J