Structural, energetic and lipophilic analysis of SARS-CoV-2 non-structural protein 9 (NSP9)

Abstract In SARS-CoV-2 replication complex, the Non-structural protein 9 (Nsp9) is an important RNA binding subunit in the RNA-synthesizing machinery. The dimeric forms of coronavirus Nsp9 increase their nucleic acid binding affinity and the N-finger motif appears to play a critical role in dimeriza...

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Autores principales:	Jéssica de O. Araújo, Silvana Pinheiro, William J. Zamora, Cláudio Nahum Alves, Jerônimo Lameira, Anderson H. Lima
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7731929feb7a485ab9773988c13d99ca
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spelling	oai:doaj.org-article:7731929feb7a485ab9773988c13d99ca2021-11-28T12:17:39ZStructural, energetic and lipophilic analysis of SARS-CoV-2 non-structural protein 9 (NSP9)10.1038/s41598-021-02366-02045-2322https://doaj.org/article/7731929feb7a485ab9773988c13d99ca2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02366-0https://doaj.org/toc/2045-2322Abstract In SARS-CoV-2 replication complex, the Non-structural protein 9 (Nsp9) is an important RNA binding subunit in the RNA-synthesizing machinery. The dimeric forms of coronavirus Nsp9 increase their nucleic acid binding affinity and the N-finger motif appears to play a critical role in dimerization. Here, we present a structural, lipophilic and energetic study about the Nsp9 dimer of SARS-CoV-2 through computational methods that complement hydrophobicity scales of amino acids with molecular dynamics simulations. Additionally, we presented a virtual N-finger mutation to investigate whether this motif contributes to dimer stability. The results reveal for the native dimer that the N-finger contributes favorably through hydrogen bond interactions and two amino acids bellowing to the hydrophobic region, Leu45 and Leu106, are crucial in the formation of the cavity for potential drug binding. On the other hand, Gly100 and Gly104, are responsible for stabilizing the α-helices and making the dimer interface remain stable in both, native and mutant (without N-finger motif) systems. Besides, clustering results for the native dimer showed accessible cavities to drugs. In addition, the energetic and lipophilic analysis reveal that the higher binding energy in the native dimer can be deduced since it is more lipophilic than the mutant one, increasing non-polar interactions, which is in line with the result of MM-GBSA and SIE approaches where the van der Waals energy term has the greatest weight in the stability of the native dimer. Overall, we provide a detailed study on the Nsp9 dimer of SARS-CoV-2 that may aid in the development of new strategies for the treatment and prevention of COVID-19.Jéssica de O. AraújoSilvana PinheiroWilliam J. ZamoraCláudio Nahum AlvesJerônimo LameiraAnderson H. LimaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jéssica de O. Araújo Silvana Pinheiro William J. Zamora Cláudio Nahum Alves Jerônimo Lameira Anderson H. Lima Structural, energetic and lipophilic analysis of SARS-CoV-2 non-structural protein 9 (NSP9)
description	Abstract In SARS-CoV-2 replication complex, the Non-structural protein 9 (Nsp9) is an important RNA binding subunit in the RNA-synthesizing machinery. The dimeric forms of coronavirus Nsp9 increase their nucleic acid binding affinity and the N-finger motif appears to play a critical role in dimerization. Here, we present a structural, lipophilic and energetic study about the Nsp9 dimer of SARS-CoV-2 through computational methods that complement hydrophobicity scales of amino acids with molecular dynamics simulations. Additionally, we presented a virtual N-finger mutation to investigate whether this motif contributes to dimer stability. The results reveal for the native dimer that the N-finger contributes favorably through hydrogen bond interactions and two amino acids bellowing to the hydrophobic region, Leu45 and Leu106, are crucial in the formation of the cavity for potential drug binding. On the other hand, Gly100 and Gly104, are responsible for stabilizing the α-helices and making the dimer interface remain stable in both, native and mutant (without N-finger motif) systems. Besides, clustering results for the native dimer showed accessible cavities to drugs. In addition, the energetic and lipophilic analysis reveal that the higher binding energy in the native dimer can be deduced since it is more lipophilic than the mutant one, increasing non-polar interactions, which is in line with the result of MM-GBSA and SIE approaches where the van der Waals energy term has the greatest weight in the stability of the native dimer. Overall, we provide a detailed study on the Nsp9 dimer of SARS-CoV-2 that may aid in the development of new strategies for the treatment and prevention of COVID-19.
format	article
author	Jéssica de O. Araújo Silvana Pinheiro William J. Zamora Cláudio Nahum Alves Jerônimo Lameira Anderson H. Lima
author_facet	Jéssica de O. Araújo Silvana Pinheiro William J. Zamora Cláudio Nahum Alves Jerônimo Lameira Anderson H. Lima
author_sort	Jéssica de O. Araújo
title	Structural, energetic and lipophilic analysis of SARS-CoV-2 non-structural protein 9 (NSP9)
title_short	Structural, energetic and lipophilic analysis of SARS-CoV-2 non-structural protein 9 (NSP9)
title_full	Structural, energetic and lipophilic analysis of SARS-CoV-2 non-structural protein 9 (NSP9)
title_fullStr	Structural, energetic and lipophilic analysis of SARS-CoV-2 non-structural protein 9 (NSP9)
title_full_unstemmed	Structural, energetic and lipophilic analysis of SARS-CoV-2 non-structural protein 9 (NSP9)
title_sort	structural, energetic and lipophilic analysis of sars-cov-2 non-structural protein 9 (nsp9)
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7731929feb7a485ab9773988c13d99ca
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Structural, energetic and lipophilic analysis of SARS-CoV-2 non-structural protein 9 (NSP9)

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