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Effect of Double Mutation (L452R and E484Q) on the Binding Affinity of Monoclonal Antibodies (mAbs) against the RBD—A Target for Vaccine Development
The COVID-19 pandemic, caused by SARS-CoV-2, emerges as a global health problem, as the viral genome is evolving rapidly to form several variants. Advancement and progress in the development of effective vaccines and neutralizing monoclonal antibodies are promising to combat viral infections. In the...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9860914/ https://www.ncbi.nlm.nih.gov/pubmed/36679867 http://dx.doi.org/10.3390/vaccines11010023 |
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author | Gupta, Deepali Kumar, Mukesh Sharma, Priyanka Mohan, Trishala Prakash, Amresh Kumari, Renu Kaur, Punit |
author_facet | Gupta, Deepali Kumar, Mukesh Sharma, Priyanka Mohan, Trishala Prakash, Amresh Kumari, Renu Kaur, Punit |
author_sort | Gupta, Deepali |
collection | PubMed |
description | The COVID-19 pandemic, caused by SARS-CoV-2, emerges as a global health problem, as the viral genome is evolving rapidly to form several variants. Advancement and progress in the development of effective vaccines and neutralizing monoclonal antibodies are promising to combat viral infections. In the current scenario, several lineages containing “co-mutations” in the receptor-binding domain (RBD) region of the spike (S) protein are imposing new challenges. Co-occurrence of some co-mutations includes delta (L452R/T478K), kappa (L452R/E484Q), and a common mutation in both beta and gamma variants (E484K/N501Y). The effect of co-mutants (L452R/E484Q) on human angiotensin-converting enzyme 2 (hACE2) binding has already been elucidated. Here, for the first time, we investigated the role of these RBD co-mutations (L452R/E484Q) on the binding affinity of mAbs by adopting molecular dynamics (MD) simulation and free-energy binding estimation. The results obtained from our study suggest that the structural and dynamic changes introduced by these co-mutations reduce the binding affinity of the viral S protein to monoclonal antibodies (mAbs). The structural changes imposed by L452R create a charged patch near the interfacial surface that alters the affinity towards mAbs. In E484Q mutation, polar negatively charged E484 helps in the formation of electrostatic interaction, while the neutrally charged Q residue affects the interaction by forming repulsive forces. MD simulations along with molecular mechanics-generalized Born surface area (MMGBSA) studies revealed that the REGN 10933, BD-368-2, and S2M11 complexes have reduced binding affinity towards the double-mutant RBD. This indicates that their mutant (MT) structures have a stronger ability to escape from most antibodies than the wild type (WT). However, EY6A Ab showed higher affinity towards the double MT-RBD complex as compared to the WT. However, no significant effect of the per-residue contribution of double-mutated residues was observed, as this mAb does not interact with the region harboring L452 and E484 residues. |
format | Online Article Text |
id | pubmed-9860914 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-98609142023-01-22 Effect of Double Mutation (L452R and E484Q) on the Binding Affinity of Monoclonal Antibodies (mAbs) against the RBD—A Target for Vaccine Development Gupta, Deepali Kumar, Mukesh Sharma, Priyanka Mohan, Trishala Prakash, Amresh Kumari, Renu Kaur, Punit Vaccines (Basel) Article The COVID-19 pandemic, caused by SARS-CoV-2, emerges as a global health problem, as the viral genome is evolving rapidly to form several variants. Advancement and progress in the development of effective vaccines and neutralizing monoclonal antibodies are promising to combat viral infections. In the current scenario, several lineages containing “co-mutations” in the receptor-binding domain (RBD) region of the spike (S) protein are imposing new challenges. Co-occurrence of some co-mutations includes delta (L452R/T478K), kappa (L452R/E484Q), and a common mutation in both beta and gamma variants (E484K/N501Y). The effect of co-mutants (L452R/E484Q) on human angiotensin-converting enzyme 2 (hACE2) binding has already been elucidated. Here, for the first time, we investigated the role of these RBD co-mutations (L452R/E484Q) on the binding affinity of mAbs by adopting molecular dynamics (MD) simulation and free-energy binding estimation. The results obtained from our study suggest that the structural and dynamic changes introduced by these co-mutations reduce the binding affinity of the viral S protein to monoclonal antibodies (mAbs). The structural changes imposed by L452R create a charged patch near the interfacial surface that alters the affinity towards mAbs. In E484Q mutation, polar negatively charged E484 helps in the formation of electrostatic interaction, while the neutrally charged Q residue affects the interaction by forming repulsive forces. MD simulations along with molecular mechanics-generalized Born surface area (MMGBSA) studies revealed that the REGN 10933, BD-368-2, and S2M11 complexes have reduced binding affinity towards the double-mutant RBD. This indicates that their mutant (MT) structures have a stronger ability to escape from most antibodies than the wild type (WT). However, EY6A Ab showed higher affinity towards the double MT-RBD complex as compared to the WT. However, no significant effect of the per-residue contribution of double-mutated residues was observed, as this mAb does not interact with the region harboring L452 and E484 residues. MDPI 2022-12-22 /pmc/articles/PMC9860914/ /pubmed/36679867 http://dx.doi.org/10.3390/vaccines11010023 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Gupta, Deepali Kumar, Mukesh Sharma, Priyanka Mohan, Trishala Prakash, Amresh Kumari, Renu Kaur, Punit Effect of Double Mutation (L452R and E484Q) on the Binding Affinity of Monoclonal Antibodies (mAbs) against the RBD—A Target for Vaccine Development |
title | Effect of Double Mutation (L452R and E484Q) on the Binding Affinity of Monoclonal Antibodies (mAbs) against the RBD—A Target for Vaccine Development |
title_full | Effect of Double Mutation (L452R and E484Q) on the Binding Affinity of Monoclonal Antibodies (mAbs) against the RBD—A Target for Vaccine Development |
title_fullStr | Effect of Double Mutation (L452R and E484Q) on the Binding Affinity of Monoclonal Antibodies (mAbs) against the RBD—A Target for Vaccine Development |
title_full_unstemmed | Effect of Double Mutation (L452R and E484Q) on the Binding Affinity of Monoclonal Antibodies (mAbs) against the RBD—A Target for Vaccine Development |
title_short | Effect of Double Mutation (L452R and E484Q) on the Binding Affinity of Monoclonal Antibodies (mAbs) against the RBD—A Target for Vaccine Development |
title_sort | effect of double mutation (l452r and e484q) on the binding affinity of monoclonal antibodies (mabs) against the rbd—a target for vaccine development |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9860914/ https://www.ncbi.nlm.nih.gov/pubmed/36679867 http://dx.doi.org/10.3390/vaccines11010023 |
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