Computational Biological Center, IBM Thomas J. Watson Research, Yorktown Heights, New York 10598, United States.
J Med Chem. 2022 Feb 24;65(4):2820-2826. doi: 10.1021/acs.jmedchem.1c00311. Epub 2021 Apr 9.
The highly infectious SARS-CoV-2 variant B.1.351 that first emerged in South Africa with triple mutations (N501Y, K417N, and E484K) is globally worrisome. It is known that N501Y and E484K can enhance binding between the coronavirus receptor domain (RBD) and human ACE2. However, the K417N mutation appears to be unfavorable as it removes one interfacial salt bridge. Here, we show that despite the decrease in binding affinity (1.48 kcal/mol) between RBD and ACE2, the K417N mutation abolishes a buried interfacial salt bridge between the RBD and neutralizing antibody CB6. This substantially reduces their binding energy by 9.59 kcal/mol, thus facilitating the process by which the variant efficiently eludes CB6 (including many other antibodies). Our theoretical predictions agree with existing experimental findings. Harnessing the revealed molecular mechanisms makes it possible to redesign therapeutic antibodies, thus making them more efficacious.
首先在南非出现的具有三重突变（N501Y、K417N 和 E484K）的高传染性 SARS-CoV-2 变体 B.1.351 令全球担忧。已知 N501Y 和 E484K 可以增强冠状病毒受体结构域（RBD）与人 ACE2 之间的结合。然而，K417N 突变似乎不利，因为它消除了一个界面盐桥。在这里，我们表明，尽管 RBD 和 ACE2 之间的结合亲和力（1.48 kcal/mol）下降，但 K417N 突变会使 RBD 和中和抗体 CB6 之间的埋藏界面盐桥失效。这将它们的结合能降低了 9.59 kcal/mol，从而促进了变体有效逃避 CB6（包括许多其他抗体）的过程。我们的理论预测与现有的实验结果一致。利用揭示的分子机制，可以重新设计治疗性抗体，从而提高它们的疗效。
