Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

E484K mutation in SARS-CoV-2 RBD enhances binding affinity with hACE2 but reduces interactions with neutralizing antibodies and nanobodies: Binding free energy calculation studies

Wei Bu Wang, Yu Liang, Yu Qin Jin, Jing Zhang, View ORCID ProfileJi Guo Su, Qi Ming Li
doi: https://doi.org/10.1101/2021.02.17.431566
Wei Bu Wang
1Key Laboratory for Microstructural Material Physics of Hebei Province, School of Science, Yanshan University, Qinhuangdao 066004, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yu Liang
2The Sixth Laboratory, National Vaccine and Serum Institute, Beijing 101111, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yu Qin Jin
2The Sixth Laboratory, National Vaccine and Serum Institute, Beijing 101111, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jing Zhang
2The Sixth Laboratory, National Vaccine and Serum Institute, Beijing 101111, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ji Guo Su
1Key Laboratory for Microstructural Material Physics of Hebei Province, School of Science, Yanshan University, Qinhuangdao 066004, China
2The Sixth Laboratory, National Vaccine and Serum Institute, Beijing 101111, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ji Guo Su
  • For correspondence: liqiming189@163.com jiguosu@ysu.edu.cn
Qi Ming Li
2The Sixth Laboratory, National Vaccine and Serum Institute, Beijing 101111, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: liqiming189@163.com jiguosu@ysu.edu.cn
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

The pandemic of the COVID-19 disease caused by SARS-CoV-2 has led to more than 100 million infections and over 2 million deaths worldwide. The progress in the developments of effective vaccines and neutralizing antibody therapeutics brings hopes to eliminate the threat of COVID-19. However, SARS-CoV-2 continues to mutate, and several new variants have been emerged. Among the various naturally-occurring mutations, the E484K mutation shared by both the 501Y.V2 and 501Y.V3 variants attracted serious concerns, which may potentially enhance the receptor binding affinity and reduce the immune response. In the present study, the molecular mechanism behind the impacts of E484K mutation on the binding affinity of the receptor-binding domain (RBD) with the receptor human angiotensin-converting enzyme 2 (hACE2) was investigated by using the molecular dynamics (MD) simulations combined with the molecular mechanics-generalized Born surface area (MMGBSA) method. Our results indicate that the E484K mutation results in more favorable electrostatic interactions compensating the burial of the charged and polar groups upon the binding of RBD with hACE2, which significantly improves the RBD-hACE2 binding affinity. Besides that, the E484K mutation also causes the conformational rearrangements of the loop region containing the mutant residue, which leads to more tight binding interface of RBD with hACE2 and formation of some new hydrogen bonds. The more tight binding interface and the new hydrogen bonds formation also contribute to the improved binding affinity of RBD to the receptor hACE2. In addition, six neutralizing antibodies and nanobodies complexed with RBD were selected to explore the effects of E484K mutation on the recognition of these antibodies to RBD. The simulation results show that the E484K mutation significantly reduces the binding affinities to RBD for most of the studied neutralizing antibodies, and the decrease in the binding affinities is mainly owing to the unfavorable electrostatic interactions caused by the mutation. Our studies revealed that the E484K mutation may improve the binding affinity between RBD and the receptor hACE2, implying more transmissibility of the E484K-containing variants, and weaken the binding affinities between RBD and the studied neutralizing antibodies, indicating reduced effectiveness of these antibodies. Our results provide valuable information for the effective vaccine development and antibody drugs design.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted February 17, 2021.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
E484K mutation in SARS-CoV-2 RBD enhances binding affinity with hACE2 but reduces interactions with neutralizing antibodies and nanobodies: Binding free energy calculation studies
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
E484K mutation in SARS-CoV-2 RBD enhances binding affinity with hACE2 but reduces interactions with neutralizing antibodies and nanobodies: Binding free energy calculation studies
Wei Bu Wang, Yu Liang, Yu Qin Jin, Jing Zhang, Ji Guo Su, Qi Ming Li
bioRxiv 2021.02.17.431566; doi: https://doi.org/10.1101/2021.02.17.431566
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
E484K mutation in SARS-CoV-2 RBD enhances binding affinity with hACE2 but reduces interactions with neutralizing antibodies and nanobodies: Binding free energy calculation studies
Wei Bu Wang, Yu Liang, Yu Qin Jin, Jing Zhang, Ji Guo Su, Qi Ming Li
bioRxiv 2021.02.17.431566; doi: https://doi.org/10.1101/2021.02.17.431566

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Bioinformatics
Subject Areas
All Articles
  • Animal Behavior and Cognition (4381)
  • Biochemistry (9581)
  • Bioengineering (7086)
  • Bioinformatics (24844)
  • Biophysics (12597)
  • Cancer Biology (9951)
  • Cell Biology (14345)
  • Clinical Trials (138)
  • Developmental Biology (7944)
  • Ecology (12101)
  • Epidemiology (2067)
  • Evolutionary Biology (15984)
  • Genetics (10921)
  • Genomics (14732)
  • Immunology (9869)
  • Microbiology (23645)
  • Molecular Biology (9477)
  • Neuroscience (50838)
  • Paleontology (369)
  • Pathology (1539)
  • Pharmacology and Toxicology (2681)
  • Physiology (4013)
  • Plant Biology (8655)
  • Scientific Communication and Education (1508)
  • Synthetic Biology (2391)
  • Systems Biology (6427)
  • Zoology (1346)