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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.
J Mol Graph Model. 2021 12; 109:108035.JM

Abstract

The pandemic of the COVID-19 disease caused by SARS-CoV-2 has led to more than 200 million infections and over 4 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 many 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 tighter binding interface of RBD with hACE2 and formation of some new hydrogen bonds. The tighter 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/nanobodies, 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/nanobodies, indicating reduced effectiveness of these antibodies/nanobodies. Our results provide valuable information for the effective vaccine development and antibody/nanobody drug design.

Authors+Show Affiliations

Key Laboratory for Microstructural Material Physics of Hebei Province, School of Science, Yanshan University, Qinhuangdao, 066004, China.The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, 101111, China.The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, 101111, China.The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, 101111, China.Key Laboratory for Microstructural Material Physics of Hebei Province, School of Science, Yanshan University, Qinhuangdao, 066004, China; The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, 101111, China. Electronic address: jiguosu@ysu.edu.cn.The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, 101111, China. Electronic address: liqiming189@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34562851

Citation

Wang, Wei Bu, et al. "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." Journal of Molecular Graphics & Modelling, vol. 109, 2021, p. 108035.
Wang WB, Liang Y, Jin YQ, et al. 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. J Mol Graph Model. 2021;109:108035.
Wang, W. B., Liang, Y., Jin, Y. Q., Zhang, J., Su, J. G., & Li, Q. M. (2021). 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. Journal of Molecular Graphics & Modelling, 109, 108035. https://doi.org/10.1016/j.jmgm.2021.108035
Wang WB, et al. 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. J Mol Graph Model. 2021;109:108035. PubMed PMID: 34562851.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Wang,Wei Bu, AU - Liang,Yu, AU - Jin,Yu Qin, AU - Zhang,Jing, AU - Su,Ji Guo, AU - Li,Qi Ming, Y1 - 2021/09/17/ PY - 2021/05/24/received PY - 2021/09/05/revised PY - 2021/09/13/accepted PY - 2021/9/26/pubmed PY - 2021/11/6/medline PY - 2021/9/25/entrez KW - All-atom molecular dynamics simulation KW - Binding affinity KW - E484K KW - Human angiotensin-converting enzyme 2 KW - Neutralizing antibodies KW - SARS-CoV-2 SP - 108035 EP - 108035 JF - Journal of molecular graphics & modelling JO - J Mol Graph Model VL - 109 N2 - The pandemic of the COVID-19 disease caused by SARS-CoV-2 has led to more than 200 million infections and over 4 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 many 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 tighter binding interface of RBD with hACE2 and formation of some new hydrogen bonds. The tighter 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/nanobodies, 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/nanobodies, indicating reduced effectiveness of these antibodies/nanobodies. Our results provide valuable information for the effective vaccine development and antibody/nanobody drug design. SN - 1873-4243 UR - https://www.unboundmedicine.com/medline/citation/34562851/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1093-3263(21)00206-0 DB - PRIME DP - Unbound Medicine ER -