Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok, 10330, Thailand.
Sci Rep. 2023 Sep 19;13(1):15476. doi: 10.1038/s41598-023-42442-1.
During the COVID-19 pandemic, SARS-CoV-2 has caused large numbers of morbidity and mortality, and the Omicron variant (B.1.1.529) was an important variant of concern. To enter human cells, the receptor-binding domain (RBD) of the S1 subunit of SARS-CoV-2 (SARS-CoV-2-RBD) binds to the peptidase domain (PD) of Angiotensin-converting enzyme 2 (ACE2) receptor. Disrupting the binding interactions between SARS-CoV-2-RBD and ACE2-PD using neutralizing antibodies is an effective COVID-19 therapeutic solution. Previous study found that Beta-27 Fab, which was obtained by digesting the full IgG antibodies that were isolated from a patient infected with SARS-CoV-2 Beta variant, can neutralize Victoria, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) variants. This study employed computational protein design and molecular dynamics (MD) to investigate and enhance the binding affinity of Beta-27 Fab to SARS-CoV-2-RBD Omicron variant. MD results show that five best designed Beta-27 Fabs (Beta-27-D01 Fab, Beta-27-D03 Fab, Beta-27-D06 Fab, Beta-27-D09 Fab and Beta-27-D10 Fab) were predicted to bind to Omicron RBD in the area, where ACE2 binds, with significantly better binding affinities than Beta-27 Fab and ACE2. Their enhanced binding affinities are mostly caused by increased binding interactions of CDR L2 and L3. They are promising candidates that could potentially be employed to disrupt the binding between ACE2 and Omicron RBD.
在 COVID-19 大流行期间，SARS-CoV-2 导致了大量的发病率和死亡率，Omicron 变体（B.1.1.529）是一个令人关注的重要变体。为了进入人体细胞，SARS-CoV-2（SARS-CoV-2-RBD）的 S1 亚单位的受体结合域（RBD）与血管紧张素转换酶 2（ACE2）受体的肽酶域（PD）结合。使用中和抗体破坏 SARS-CoV-2-RBD 和 ACE2-PD 之间的结合相互作用是一种有效的 COVID-19 治疗方法。先前的研究发现，Beta-27 Fab 是通过消化从感染 SARS-CoV-2 Beta 变体的患者中分离出的全长 IgG 抗体获得的，可以中和 Victoria、Alpha（B.1.1.7）、Beta（B.1.351）、Gamma（P.1）和 Delta（B.1.617.2）变体。本研究采用计算蛋白质设计和分子动力学（MD）来研究和增强 Beta-27 Fab 与 SARS-CoV-2-RBD Omicron 变体的结合亲和力。MD 结果表明，预测五个最佳设计的 Beta-27 Fab（Beta-27-D01 Fab、Beta-27-D03 Fab、Beta-27-D06 Fab、Beta-27-D09 Fab 和 Beta-27-D10 Fab）可以结合到 ACE2 结合的 Omicron RBD 区域，具有比 Beta-27 Fab 和 ACE2 更好的结合亲和力。它们增强的结合亲和力主要是由于 CDR L2 和 L3 的结合相互作用增加所致。它们是有前途的候选者，有可能被用于破坏 ACE2 和 Omicron RBD 之间的结合。
