武汉株 SARS-CoV-2 的受体结合域与奥密克戎 B.1.1.529 相比，对人 ACE2 的可变结构具有更高的亲和力。
Receptor binding domain of SARS-CoV-2 from Wuhan strain to Omicron B.1.1.529 attributes increased affinity to variable structures of human ACE2.
机构信息
Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan 45412, Saudi Arabia; Centre of Molecular Medicine and Diagnostics (COMManD), Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai - 600077, India.
Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia.
出版信息
J Infect Public Health. 2022 Jul;15(7):781-787. doi: 10.1016/j.jiph.2022.06.004. Epub 2022 Jun 16.
BACKGROUND
COVID-19 is an infectious disease declared as a global pandemic caused by SARS-CoV-2 virus. Genomic changes in the receptor binding domain (RBD) region of SARS-CoV-2 led to an increased, infectivity in humans through interaction with the angiotensin-converting enzyme2 (ACE2) receptor. Simultaneously, the genetic variants in ACE2 provide an opportunity for SARS-CoV-2 infection and severity. We demonstrate the binding efficiencies of RBDs of SARS-CoV-2 strain with ACE2 variants of the human host.
METHODOLOGY
A Total of 615 SARS-CoV-2 genomes were retrieved from repository. Eighteen variations were identified contributing to structural changes in RBD that are distributed in 615 isolates. An analyses of 285 single nucleotide variances at the coding region of the ACE2 receptor showed 34 to be pathogenic. Homology models of 34 ACE2 and 18 RBD structures were constructed with 34 and 18 structural variants, respectively. Protein docking of 612 (34 *18) ACE2-RBD complexes showed variable affinities compared to wildtype Wuhan's and other SARS-CoV-2 RBDs, including Omicron B.1.1.529. Finally, molecular dynamic simulation was performed to determine the stability of the complexes.
RESULTS
Among 612, the top 3 complexes showing least binding energy were selected. The ACE2 with rs961360700 variant showed the least binding energy (-895.2 Kcal/mol) on binding with the RBD of Phe160Ser variant compared to Wuhan's RBD complex. Interestingly, the binding energy of RBD of Omicron B.1.1.529 with ACE2 (rs961360700) structure showed least binding energy of -1010 Kcal/mol. Additionally, molecular dynamics showed structure stability for all the analysed complexes with the RMSD (0.22-0.26 nm), RMSF (0.11-0.13 nm), and Rg (2.53-2.56 nm).
CONCLUSION
In conclusion, our investigation highlights the clinical variants contributing to structural variants in ACE2 receptors that lead to efficient binding of SARS-CoV-2. Therefore, screening of these ACE2 polymorphisms will help detect COVID-19 risk population so as to provide additional care and for safe management.
背景
COVID-19 是一种传染病，被宣布为一种由 SARS-CoV-2 病毒引起的全球大流行。SARS-CoV-2 受体结合域（RBD）区域的基因组变化导致其通过与血管紧张素转换酶 2（ACE2）受体相互作用而在人类中具有更高的感染性。同时，ACE2 的遗传变异为 SARS-CoV-2 感染和严重程度提供了机会。我们展示了 SARS-CoV-2 株的 RBD 与人类宿主 ACE2 变体的结合效率。
方法
从存储库中总共检索了 615 个 SARS-CoV-2 基因组。鉴定出 18 种变异，这些变异导致 RBD 结构发生变化，分布在 615 个分离株中。对 ACE2 受体编码区的 285 个单核苷酸变异进行分析，显示 34 个具有致病性。构建了 34 个 ACE2 和 18 个 RBD 结构的同源模型，分别具有 34 个和 18 个结构变体。与野生型武汉株和其他 SARS-CoV-2 RBD 相比，包括奥密克戎 B.1.1.529 在内，对 612 个（34×18）ACE2-RBD 复合物的蛋白对接显示出不同的亲和力。最后，进行了分子动力学模拟以确定复合物的稳定性。
结果
在 612 个中，选择了结合能最低的前 3 个复合物。与武汉 RBD 复合物相比，ACE2 与 rs961360700 变体结合时，RBD 的 Phe160Ser 变体的结合能最低（-895.2 Kcal/mol）。有趣的是，奥密克戎 B.1.1.529 的 RBD 与 ACE2（rs961360700）结构的结合能显示出最低的结合能-1010 Kcal/mol。此外，分子动力学显示所有分析的复合物都具有结构稳定性，均方根偏差（RMSD）（0.22-0.26nm）、均方根波动（RMSF）（0.11-0.13nm）和旋转半径（Rg）（2.53-2.56nm）。
结论
总之，我们的研究强调了导致 ACE2 受体结构变异的临床变异，这些变异导致 SARS-CoV-2 的有效结合。因此，筛选这些 ACE2 多态性将有助于发现 COVID-19 风险人群，从而提供额外的护理和安全管理。
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