In Silico Investigation of the New UK (B.1.1.7) and South African (501Y.V2) SARS-CoV-2 Variants with a Focus at the ACE2-Spike RBD Interface.
In Silico Investigation of the New UK (B.1.1.7) and South African (501Y.V2) SARS-CoV-2 Variants with a Focus at the ACE2-Spike RBD Interface.
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DOI：
10.3390/ijms22041695
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发表时间：
2021-02-08
影响因子：
5.6
通讯作者：
Khatib AM
中科院分区：
文献类型：
--
作者：
Villoutreix BO;Calvez V;Marcelin AG;Khatib AM
SARS-CoV-2利用血管紧张素转换酶2（ACE 2）作为受体侵入细胞。据报道，英国和南非的毒株可能具有更高的传播能力，最终部分原因是SARS-CoV-2刺突蛋白上的氨基酸取代。致病性似乎有所改变，但仍在调查中。在这里，我们使用了与部分ACE 2受体共结晶的Spike RBD结构域的实验结构，几种计算机模拟方法和最近报道的大量实验数据来分析三个氨基酸替换（Spike K417 N，E484 K，N501 Y）对ACE 2结合的可能影响。我们发现，在界面的这个区域中的N501 Y替换（存在于英国和南非菌株中）应该有利于与ACE 2的相互作用，而K417 N和E484 K替换（南非菌株）似乎是中性的，甚至是不利的。目前尚不清楚南非菌株中的N501 Y置换是否可以在ACE 2结合方面抵消K417 N和E484 K刺突置换。我们的研究结果表明，英国菌株应该有更高的亲和力对ACE 2，因此可能增加的传播性和可能的致病性。如果南非菌株确实具有高传播水平，这可能是由于N501 Y替换和/或位于直接Spike-ACE 2界面之外的区域中的替换，但与K417 N和E484 K替换无关。然而，应注意，刺突位置484处的氨基酸变化可导致病毒从中和抗体逃逸。此外，这些氨基酸取代似乎不会诱导刺突蛋白的该区域中的主要结构变化。这种结构-功能研究使我们能够合理化英国菌株的一些观察结果，但对南非菌株提出了问题。
SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) as a receptor to invade cells. It has been reported that the UK and South African strains may have higher transmission capabilities, eventually in part due to amino acid substitutions on the SARS-CoV-2 Spike protein. The pathogenicity seems modified but is still under investigation. Here we used the experimental structure of the Spike RBD domain co-crystallized with part of the ACE2 receptor, several in silico methods and numerous experimental data reported recently to analyze the possible impacts of three amino acid replacements (Spike K417N, E484K, N501Y) with regard to ACE2 binding. We found that the N501Y replacement in this region of the interface (present in both the UK and South African strains) should be favorable for the interaction with ACE2, while the K417N and E484K substitutions (South African strain) would seem neutral or even unfavorable. It is unclear if the N501Y substitution in the South African strain could counterbalance the K417N and E484K Spike replacements with regard to ACE2 binding. Our finding suggests that the UK strain should have higher affinity toward ACE2 and therefore likely increased transmissibility and possibly pathogenicity. If indeed the South African strain has a high transmission level, this could be due to the N501Y replacement and/or to substitutions in regions located outside the direct Spike–ACE2 interface but not so much to the K417N and E484K replacements. Yet, it should be noted that amino acid changes at Spike position 484 can lead to viral escape from neutralizing antibodies. Further, these amino acid substitutions do not seem to induce major structural changes in this region of the Spike protein. This structure–function study allows us to rationalize some observations made for the UK strain but raises questions for the South African strain.
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影响因子：
14.9
作者：
Kuriata A;Gierut AM;Oleniecki T;Ciemny MP;Kolinski A;Kurcinski M;Kmiecik S
通讯作者：
Kmiecik S
影响因子：
5.6
作者：
Lopez-Lopez, Edgar;Bajorath, Juergen;Medina-Franco, Jose L.
通讯作者：
Medina-Franco, Jose L.
影响因子：
--
作者：
Hulswit RJ;de Haan CA;Bosch BJ
通讯作者：
Bosch BJ
影响因子：
6.8
作者：
Kucukkal TG;Petukh M;Li L;Alexov E
通讯作者：
Alexov E
影响因子：
4.6
作者：
Isabel, Sandra;Grana-Miraglia, Lucia;Poutanen, Susan M.
通讯作者：
Poutanen, Susan M.