Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait, Kuwait.
Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait, Kuwait.
Comb Chem High Throughput Screen. 2023;26(3):589-594. doi: 10.2174/1386207325666220607145225.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the lower respiratory tract by binding to angiotensin-converting enzyme 2 (ACE2) via its S-protein. Recent emerging SARS-CoV-2 variants from the United Kingdom (B.1.1.7) and South Africa (501Y.V2) are spreading worldwide at an alarming rate. The new variants have manifested amino acid substitution K417N, E484K, and N501Y on the RBD domain that binds to ACE2. These mutations may influence the binding of the S-protein to ACE2 and affect viral entry into the host cell.
In this study, we modelled the amino acid substitutions on the S-protein and utilised the HADDOCK server to assess the S-protein RBD domain binding with ACE2. Additionally, we calculated the binding affinity of ACE2 to S-protein WT, B.1.1.7 and 501Y.V2 variants using Molecular Mechanics-Generalized Born Surface Area (MM/GBSA).
We demonstrated that the S-protein of both variants possesses a higher binding affinity to ACE2 than WT, with the South African 501Y.V2 being more infective than the B.1.1.7 that originated in the United Kingdom.
The South African 501Y.V2 variant presents three amino acid substitutions that changed the H-bonding network, resulting in a higher affinity to ACE2, indicating that the 501Y.V2 strain is more infective than the B.1.1.7 strain.
严重急性呼吸系统综合症冠状病毒 2（SARS-CoV-2）通过其 S 蛋白与血管紧张素转换酶 2（ACE2）结合，从而影响下呼吸道。源自英国（B.1.1.7）和南非（501Y.V2）的新 SARS-CoV-2 变体正在以惊人的速度在全球范围内传播。新变体在 RBD 结构域上表现出与 ACE2 结合的氨基酸取代 K417N、E484K 和 N501Y。这些突变可能会影响 S 蛋白与 ACE2 的结合，并影响病毒进入宿主细胞。
在这项研究中，我们对 S 蛋白上的氨基酸取代进行建模，并利用 HADDOCK 服务器评估 S 蛋白 RBD 结构域与 ACE2 的结合。此外，我们使用分子力学-广义 Born 表面积（MM/GBSA）计算 ACE2 与 S 蛋白 WT、B.1.1.7 和 501Y.V2 变体的结合亲和力。
我们证明了两种变体的 S 蛋白对 ACE2 的结合亲和力均高于 WT，南非 501Y.V2 比源自英国的 B.1.1.7 变体更具感染力。
南非 501Y.V2 变体出现三个氨基酸取代，改变了氢键网络，导致与 ACE2 的亲和力更高，表明 501Y.V2 株比 B.1.1.7 株更具感染力。
