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通过计算设计，Fab CC12.3 对 SARS-CoV-2 的预测结合亲和力显著优于人 ACE2 受体。

Computational redesign of Fab CC12.3 with substantially better predicted binding affinity to SARS-CoV-2 than human ACE2 receptor.

机构信息

Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok, 10330, Thailand.

Department of Biochemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok, 10330, Thailand.

出版信息

Sci Rep. 2021 Nov 12;11(1):22202. doi: 10.1038/s41598-021-00684-x.

DOI:10.1038/s41598-021-00684-x
PMID:34772947
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8590000/
Abstract

SARS-CoV-2 is responsible for COVID-19 pandemic, causing large numbers of cases and deaths. It initiates entry into human cells by binding to the peptidase domain of angiotensin-converting enzyme 2 (ACE2) receptor via its receptor binding domain of S1 subunit of spike protein (SARS-CoV-2-RBD). Employing neutralizing antibodies to prevent binding between SARS-CoV-2-RBD and ACE2 is an effective COVID-19 therapeutic solution. Previous studies found that CC12.3 is a highly potent neutralizing antibody that was isolated from a SARS-CoV-2 infected patient, and its Fab fragment (Fab CC12.3) bound to SARS-CoV-2-RBD with comparable binding affinity to ACE2. To enhance its binding affinity, we employed computational protein design to redesign all CDRs of Fab CC12.3 and molecular dynamics (MD) to validate their predicted binding affinities by the MM-GBSA method. MD results show that the predicted binding affinities of the three best designed Fabs CC12.3 (CC12.3-D02, CC12.3-D05, and CC12.3-D08) are better than those of Fab CC12.3 and ACE2. Additionally, our results suggest that enhanced binding affinities of CC12.3-D02, CC12.3-D05, and CC12.3-D08 are caused by increased SARS-CoV-2-RBD binding interactions of CDRs L1 and L3. This study redesigned neutralizing antibodies with better predicted binding affinities to SARS-CoV-2-RBD than Fab CC12.3 and ACE2. They are promising candidates as neutralizing antibodies against SARS-CoV-2.

摘要

SARS-CoV-2 引发了 COVID-19 大流行，导致大量病例和死亡。它通过其刺突蛋白（SARS-CoV-2-RBD）S1 亚基的受体结合域与血管紧张素转换酶 2（ACE2）受体的肽酶结构域结合，从而启动进入人体细胞的过程。利用中和抗体防止 SARS-CoV-2-RBD 和 ACE2 之间的结合是一种有效的 COVID-19 治疗方法。先前的研究发现，CC12.3 是一种从 SARS-CoV-2 感染患者中分离出来的高效中和抗体，其 Fab 片段（Fab CC12.3）与 SARS-CoV-2-RBD 的结合亲和力与 ACE2 相当。为了提高其结合亲和力，我们采用计算蛋白质设计重新设计了 Fab CC12.3 的所有 CDR，并采用分子动力学（MD）通过 MM-GBSA 方法验证其预测的结合亲和力。MD 结果表明，三个最佳设计的 Fab CC12.3（CC12.3-D02、CC12.3-D05 和 CC12.3-D08）的预测结合亲和力优于 Fab CC12.3 和 ACE2。此外，我们的结果表明，CC12.3-D02、CC12.3-D05 和 CC12.3-D08 的结合亲和力增强是由于 CDR L1 和 L3 与 SARS-CoV-2-RBD 的结合相互作用增加所致。这项研究重新设计了具有比 Fab CC12.3 和 ACE2 更好的预测结合亲和力的中和抗体，以 SARS-CoV-2-RBD 为靶点。它们是对抗 SARS-CoV-2 的有前途的候选中和抗体。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5914/8590000/93f905187f54/41598_2021_684_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5914/8590000/5a7efb9b0e2e/41598_2021_684_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5914/8590000/f4b4f6d4731c/41598_2021_684_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5914/8590000/317f3c312ea2/41598_2021_684_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5914/8590000/af485567b541/41598_2021_684_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5914/8590000/93f905187f54/41598_2021_684_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5914/8590000/5a7efb9b0e2e/41598_2021_684_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5914/8590000/f4b4f6d4731c/41598_2021_684_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5914/8590000/317f3c312ea2/41598_2021_684_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5914/8590000/af485567b541/41598_2021_684_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5914/8590000/93f905187f54/41598_2021_684_Fig5_HTML.jpg

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