Unraveling the stability landscape of mutations in the SARS-CoV-2 receptor-binding domain

Abstract The interaction between the receptor-binding domain (RBD) of the SARS-CoV-2 spike glycoprotein and the ACE2 enzyme is believed to be the entry point of the virus into various cells in the body, including the lungs, heart, liver, and kidneys. The current focus of several therapeutic design e...

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Autores principales:	Mohamed Raef Smaoui, Hamdi Yahyaoui
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b8913412ea3042efbb8a5bc3b430b8df
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spelling	oai:doaj.org-article:b8913412ea3042efbb8a5bc3b430b8df2021-12-02T17:16:04ZUnraveling the stability landscape of mutations in the SARS-CoV-2 receptor-binding domain10.1038/s41598-021-88696-52045-2322https://doaj.org/article/b8913412ea3042efbb8a5bc3b430b8df2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88696-5https://doaj.org/toc/2045-2322Abstract The interaction between the receptor-binding domain (RBD) of the SARS-CoV-2 spike glycoprotein and the ACE2 enzyme is believed to be the entry point of the virus into various cells in the body, including the lungs, heart, liver, and kidneys. The current focus of several therapeutic design efforts explores attempts at affecting the binding potential between the two proteins to limit the activity of the virus and disease progression. In this work, we analyze the stability of the spike protein under all possible single-point mutations in the RBD and computationally explore mutations that can affect the binding with the ACE2 enzyme. We unravel the mutation landscape of the receptor region and assess the toxicity potential of single and multi-point mutations, generating insights for future vaccine efforts on mutations that might further stabilize the spike protein and increase its infectivity. We developed a tool, called SpikeMutator, to construct full atomic protein structures of the mutant spike proteins and shared a database of 3800 single-point mutant structures. We analyzed the recent 65,000 reported spike sequences across the globe and observed the emergence of stable multi-point mutant structures. Using the landscape, we searched through 7.5 million possible 2-point mutation combinations and report that the (R355D K424E) mutation produces one of the strongest spike proteins that therapeutic efforts should investigate for the sake of developing effective vaccines.Mohamed Raef SmaouiHamdi YahyaouiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mohamed Raef Smaoui Hamdi Yahyaoui Unraveling the stability landscape of mutations in the SARS-CoV-2 receptor-binding domain
description	Abstract The interaction between the receptor-binding domain (RBD) of the SARS-CoV-2 spike glycoprotein and the ACE2 enzyme is believed to be the entry point of the virus into various cells in the body, including the lungs, heart, liver, and kidneys. The current focus of several therapeutic design efforts explores attempts at affecting the binding potential between the two proteins to limit the activity of the virus and disease progression. In this work, we analyze the stability of the spike protein under all possible single-point mutations in the RBD and computationally explore mutations that can affect the binding with the ACE2 enzyme. We unravel the mutation landscape of the receptor region and assess the toxicity potential of single and multi-point mutations, generating insights for future vaccine efforts on mutations that might further stabilize the spike protein and increase its infectivity. We developed a tool, called SpikeMutator, to construct full atomic protein structures of the mutant spike proteins and shared a database of 3800 single-point mutant structures. We analyzed the recent 65,000 reported spike sequences across the globe and observed the emergence of stable multi-point mutant structures. Using the landscape, we searched through 7.5 million possible 2-point mutation combinations and report that the (R355D K424E) mutation produces one of the strongest spike proteins that therapeutic efforts should investigate for the sake of developing effective vaccines.
format	article
author	Mohamed Raef Smaoui Hamdi Yahyaoui
author_facet	Mohamed Raef Smaoui Hamdi Yahyaoui
author_sort	Mohamed Raef Smaoui
title	Unraveling the stability landscape of mutations in the SARS-CoV-2 receptor-binding domain
title_short	Unraveling the stability landscape of mutations in the SARS-CoV-2 receptor-binding domain
title_full	Unraveling the stability landscape of mutations in the SARS-CoV-2 receptor-binding domain
title_fullStr	Unraveling the stability landscape of mutations in the SARS-CoV-2 receptor-binding domain
title_full_unstemmed	Unraveling the stability landscape of mutations in the SARS-CoV-2 receptor-binding domain
title_sort	unraveling the stability landscape of mutations in the sars-cov-2 receptor-binding domain
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b8913412ea3042efbb8a5bc3b430b8df
work_keys_str_mv	AT mohamedraefsmaoui unravelingthestabilitylandscapeofmutationsinthesarscov2receptorbindingdomain AT hamdiyahyaoui unravelingthestabilitylandscapeofmutationsinthesarscov2receptorbindingdomain
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Unraveling the stability landscape of mutations in the SARS-CoV-2 receptor-binding domain

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