tetano
Editor, Senior Moderator
J Med Chem
. 2021 Apr 9.
doi: 10.1021/acs.jmedchem.1c00311. Online ahead of print.
Insights into SARS-CoV-2's Mutations for Evading Human Antibodies: Sacrifice and Survival
Binquan Luan[SUP] 1 [/SUP], Tien Huynh[SUP] 1 [/SUP]
Affiliations
Abstract
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.
. 2021 Apr 9.
doi: 10.1021/acs.jmedchem.1c00311. Online ahead of print.
Insights into SARS-CoV-2's Mutations for Evading Human Antibodies: Sacrifice and Survival
Binquan Luan[SUP] 1 [/SUP], Tien Huynh[SUP] 1 [/SUP]
Affiliations
- PMID: 33834772
- DOI: 10.1021/acs.jmedchem.1c00311
Abstract
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.