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Molecular Dynamics and MM-PBSA Analysis of the SARS-CoV-2 Gamma Variant in Complex with the hACE-2 Receptor
The SARS-CoV-2 virus, since its appearance in 2019, has caused millions of cases and deaths. To date, there is no effective treatment or a vaccine that is fully protective. Despite the efforts made by governments and health institutions around the globe to control its propagation, the evolution of t...
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/PMC9000566/ https://www.ncbi.nlm.nih.gov/pubmed/35408761 http://dx.doi.org/10.3390/molecules27072370 |
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author | Cavani, Maurizio Riofrío, Walter Arnaldo Arciniega, Marcelino |
author_facet | Cavani, Maurizio Riofrío, Walter Arnaldo Arciniega, Marcelino |
author_sort | Cavani, Maurizio |
collection | PubMed |
description | The SARS-CoV-2 virus, since its appearance in 2019, has caused millions of cases and deaths. To date, there is no effective treatment or a vaccine that is fully protective. Despite the efforts made by governments and health institutions around the globe to control its propagation, the evolution of the virus has accelerated, diverging into hundreds of variants. However, not all of them are variants of concern (VoC’s). VoC’s have appeared in different regions and throughout the two years of the pandemic they have spread around the world. Specifically, in South America, the gamma variant (previously known as P.1) appeared in early 2021, bringing with it a second wave of infections. This variant contains the N501Y, E484K and K417T mutations in the receptor binding domain (RBD) of the spike protein. Although these mutations have been described experimentally, there is still no clarity regarding their role in the stabilization of the complex with the human angiotensin converting enzyme 2 (hACE-2) receptor. In this article we dissect the influence of mutations on the interaction with the hACE-2 receptor using molecular dynamics and estimations of binding affinity through a screened version of the molecular mechanics Poisson Boltzmann surface area (MM-PBSA) and interaction entropy. Our results indicate that mutations E484K and K417T compensate each other in terms of binding affinity, while the mutation N501Y promotes a more convoluted effect. This effect consists in the adoption of a cis configuration in the backbone of residue Y495 within the RBD, which in turn promotes polar interactions with the hACE-2 receptor. These results not only correlate with experimental observations and complement previous knowledge, but also expose new features associated with the specific contribution of concerned mutations. Additionally, we propose a recipe to assess the residue-specific contribution to the interaction entropy. |
format | Online Article Text |
id | pubmed-9000566 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-90005662022-04-12 Molecular Dynamics and MM-PBSA Analysis of the SARS-CoV-2 Gamma Variant in Complex with the hACE-2 Receptor Cavani, Maurizio Riofrío, Walter Arnaldo Arciniega, Marcelino Molecules Article The SARS-CoV-2 virus, since its appearance in 2019, has caused millions of cases and deaths. To date, there is no effective treatment or a vaccine that is fully protective. Despite the efforts made by governments and health institutions around the globe to control its propagation, the evolution of the virus has accelerated, diverging into hundreds of variants. However, not all of them are variants of concern (VoC’s). VoC’s have appeared in different regions and throughout the two years of the pandemic they have spread around the world. Specifically, in South America, the gamma variant (previously known as P.1) appeared in early 2021, bringing with it a second wave of infections. This variant contains the N501Y, E484K and K417T mutations in the receptor binding domain (RBD) of the spike protein. Although these mutations have been described experimentally, there is still no clarity regarding their role in the stabilization of the complex with the human angiotensin converting enzyme 2 (hACE-2) receptor. In this article we dissect the influence of mutations on the interaction with the hACE-2 receptor using molecular dynamics and estimations of binding affinity through a screened version of the molecular mechanics Poisson Boltzmann surface area (MM-PBSA) and interaction entropy. Our results indicate that mutations E484K and K417T compensate each other in terms of binding affinity, while the mutation N501Y promotes a more convoluted effect. This effect consists in the adoption of a cis configuration in the backbone of residue Y495 within the RBD, which in turn promotes polar interactions with the hACE-2 receptor. These results not only correlate with experimental observations and complement previous knowledge, but also expose new features associated with the specific contribution of concerned mutations. Additionally, we propose a recipe to assess the residue-specific contribution to the interaction entropy. MDPI 2022-04-06 /pmc/articles/PMC9000566/ /pubmed/35408761 http://dx.doi.org/10.3390/molecules27072370 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 Cavani, Maurizio Riofrío, Walter Arnaldo Arciniega, Marcelino Molecular Dynamics and MM-PBSA Analysis of the SARS-CoV-2 Gamma Variant in Complex with the hACE-2 Receptor |
title | Molecular Dynamics and MM-PBSA Analysis of the SARS-CoV-2 Gamma Variant in Complex with the hACE-2 Receptor |
title_full | Molecular Dynamics and MM-PBSA Analysis of the SARS-CoV-2 Gamma Variant in Complex with the hACE-2 Receptor |
title_fullStr | Molecular Dynamics and MM-PBSA Analysis of the SARS-CoV-2 Gamma Variant in Complex with the hACE-2 Receptor |
title_full_unstemmed | Molecular Dynamics and MM-PBSA Analysis of the SARS-CoV-2 Gamma Variant in Complex with the hACE-2 Receptor |
title_short | Molecular Dynamics and MM-PBSA Analysis of the SARS-CoV-2 Gamma Variant in Complex with the hACE-2 Receptor |
title_sort | molecular dynamics and mm-pbsa analysis of the sars-cov-2 gamma variant in complex with the hace-2 receptor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9000566/ https://www.ncbi.nlm.nih.gov/pubmed/35408761 http://dx.doi.org/10.3390/molecules27072370 |
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