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Translocation pause of remdesivir-containing primer/template RNA duplex within SARS-CoV-2’s RNA polymerase complexes

The mechanism of remdesivir incorporation into the RNA primer by the RNA-dependent RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains to be fully established at the molecular level. Here, we compare molecular dynamics (MD) simulations after incorporation of...

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Autores principales: Shi, Yuanjun, Wang, Jimin, Batista, Victor S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9640752/
https://www.ncbi.nlm.nih.gov/pubmed/36387272
http://dx.doi.org/10.3389/fmolb.2022.999291
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author Shi, Yuanjun
Wang, Jimin
Batista, Victor S.
author_facet Shi, Yuanjun
Wang, Jimin
Batista, Victor S.
author_sort Shi, Yuanjun
collection PubMed
description The mechanism of remdesivir incorporation into the RNA primer by the RNA-dependent RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains to be fully established at the molecular level. Here, we compare molecular dynamics (MD) simulations after incorporation of either remdesivir monophosphate (RMP) or adenosine monophosphate (AMP). We find that the Mg(2+)-pyrophosphate (PPi) binds more tightly to the polymerase when the added RMP is at the third primer position than in the AMP added complex. The increased affinity of Mg(2+)-PPi to the RMP-added primer/template (P/T) RNA duplex complex introduces a new hydrogen bond of a substituted cyano group in RMP with the K593 sidechain. The new interactions disrupt a switching mechanism of a hydrogen bond network that is essential for translocation of the P/T duplex product and for opening of a vacant NTP-binding site necessary for next primer extension. Furthermore, steric interactions between the sidechain of S861 and the 1′-cyano group of RMP at position i+3 hinders translocation of RMP to the i + 4 position, where i labels the insertion site. These findings are particularly valuable to guide the design of more effective inhibitors of SARS-CoV-2 RNA polymerase.
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spelling pubmed-96407522022-11-15 Translocation pause of remdesivir-containing primer/template RNA duplex within SARS-CoV-2’s RNA polymerase complexes Shi, Yuanjun Wang, Jimin Batista, Victor S. Front Mol Biosci Molecular Biosciences The mechanism of remdesivir incorporation into the RNA primer by the RNA-dependent RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains to be fully established at the molecular level. Here, we compare molecular dynamics (MD) simulations after incorporation of either remdesivir monophosphate (RMP) or adenosine monophosphate (AMP). We find that the Mg(2+)-pyrophosphate (PPi) binds more tightly to the polymerase when the added RMP is at the third primer position than in the AMP added complex. The increased affinity of Mg(2+)-PPi to the RMP-added primer/template (P/T) RNA duplex complex introduces a new hydrogen bond of a substituted cyano group in RMP with the K593 sidechain. The new interactions disrupt a switching mechanism of a hydrogen bond network that is essential for translocation of the P/T duplex product and for opening of a vacant NTP-binding site necessary for next primer extension. Furthermore, steric interactions between the sidechain of S861 and the 1′-cyano group of RMP at position i+3 hinders translocation of RMP to the i + 4 position, where i labels the insertion site. These findings are particularly valuable to guide the design of more effective inhibitors of SARS-CoV-2 RNA polymerase. Frontiers Media S.A. 2022-10-25 /pmc/articles/PMC9640752/ /pubmed/36387272 http://dx.doi.org/10.3389/fmolb.2022.999291 Text en Copyright © 2022 Shi, Wang and Batista. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Shi, Yuanjun
Wang, Jimin
Batista, Victor S.
Translocation pause of remdesivir-containing primer/template RNA duplex within SARS-CoV-2’s RNA polymerase complexes
title Translocation pause of remdesivir-containing primer/template RNA duplex within SARS-CoV-2’s RNA polymerase complexes
title_full Translocation pause of remdesivir-containing primer/template RNA duplex within SARS-CoV-2’s RNA polymerase complexes
title_fullStr Translocation pause of remdesivir-containing primer/template RNA duplex within SARS-CoV-2’s RNA polymerase complexes
title_full_unstemmed Translocation pause of remdesivir-containing primer/template RNA duplex within SARS-CoV-2’s RNA polymerase complexes
title_short Translocation pause of remdesivir-containing primer/template RNA duplex within SARS-CoV-2’s RNA polymerase complexes
title_sort translocation pause of remdesivir-containing primer/template rna duplex within sars-cov-2’s rna polymerase complexes
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9640752/
https://www.ncbi.nlm.nih.gov/pubmed/36387272
http://dx.doi.org/10.3389/fmolb.2022.999291
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