Unveiling the Effect of Low pH on the SARS-CoV-2 Main Protease by Molecular Dynamics Simulations

(1) Background: Main Protease (Mpro) is an attractive therapeutic target that acts in the replication and transcription of the SARS-CoV-2 coronavirus. Mpro is rich in residues exposed to protonation/deprotonation changes which could affect its enzymatic function. This work aimed to explore the effec...

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Autores principales:	Haruna Luz Barazorda-Ccahuana, Miroslava Nedyalkova, Francesc Mas, Sergio Madurga
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	SARS-CoV-2 Mpro pH molecular dynamics docking analysis PF-00835231 Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/dbb96d94078d44d4b0c1278f7c43fb15
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spelling	oai:doaj.org-article:dbb96d94078d44d4b0c1278f7c43fb152021-11-11T18:48:22ZUnveiling the Effect of Low pH on the SARS-CoV-2 Main Protease by Molecular Dynamics Simulations10.3390/polym132138232073-4360https://doaj.org/article/dbb96d94078d44d4b0c1278f7c43fb152021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4360/13/21/3823https://doaj.org/toc/2073-4360(1) Background: Main Protease (Mpro) is an attractive therapeutic target that acts in the replication and transcription of the SARS-CoV-2 coronavirus. Mpro is rich in residues exposed to protonation/deprotonation changes which could affect its enzymatic function. This work aimed to explore the effect of the protonation/deprotonation states of Mpro at different pHs using computational techniques. (2) Methods: The different distribution charges were obtained in all the evaluated pHs by the Semi-Grand Canonical Monte Carlo (SGCMC) method. A set of Molecular Dynamics (MD) simulations was performed to consider the different protonation/deprotonation during 250 ns, verifying the structural stability of Mpro at different pHs. (3) Results: The present findings demonstrate that active site residues and residues that allow Mpro dimerisation was not affected by pH changes. However, Mpro substrate-binding residues were altered at low pHs, allowing the increased pocket volume. Additionally, the results of the solvent distribution around S<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula>, H<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula>, N<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>δ</mi></semantics></math></inline-formula>1 and H<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>δ</mi></semantics></math></inline-formula>1 atoms of the catalytic residues Cys145 and His41 showed a low and high-water affinity at acidic pH, respectively. It which could be crucial in the catalytic mechanism of SARS-CoV-2 Mpro at low pHs. Moreover, we analysed the docking interactions of PF-00835231 from Pfizer in the preclinical phase, which shows excellent affinity with the Mpro at different pHs. (4) Conclusion: Overall, these findings indicate that SARS-CoV-2 Mpro is highly stable at acidic pH conditions, and this inhibitor could have a desirable function at this condition.Haruna Luz Barazorda-CcahuanaMiroslava NedyalkovaFrancesc MasSergio MadurgaMDPI AGarticleSARS-CoV-2 MpropHmolecular dynamicsdocking analysisPF-00835231Organic chemistryQD241-441ENPolymers, Vol 13, Iss 3823, p 3823 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	SARS-CoV-2 Mpro pH molecular dynamics docking analysis PF-00835231 Organic chemistry QD241-441
spellingShingle	SARS-CoV-2 Mpro pH molecular dynamics docking analysis PF-00835231 Organic chemistry QD241-441 Haruna Luz Barazorda-Ccahuana Miroslava Nedyalkova Francesc Mas Sergio Madurga Unveiling the Effect of Low pH on the SARS-CoV-2 Main Protease by Molecular Dynamics Simulations
description	(1) Background: Main Protease (Mpro) is an attractive therapeutic target that acts in the replication and transcription of the SARS-CoV-2 coronavirus. Mpro is rich in residues exposed to protonation/deprotonation changes which could affect its enzymatic function. This work aimed to explore the effect of the protonation/deprotonation states of Mpro at different pHs using computational techniques. (2) Methods: The different distribution charges were obtained in all the evaluated pHs by the Semi-Grand Canonical Monte Carlo (SGCMC) method. A set of Molecular Dynamics (MD) simulations was performed to consider the different protonation/deprotonation during 250 ns, verifying the structural stability of Mpro at different pHs. (3) Results: The present findings demonstrate that active site residues and residues that allow Mpro dimerisation was not affected by pH changes. However, Mpro substrate-binding residues were altered at low pHs, allowing the increased pocket volume. Additionally, the results of the solvent distribution around S<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula>, H<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula>, N<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>δ</mi></semantics></math></inline-formula>1 and H<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>δ</mi></semantics></math></inline-formula>1 atoms of the catalytic residues Cys145 and His41 showed a low and high-water affinity at acidic pH, respectively. It which could be crucial in the catalytic mechanism of SARS-CoV-2 Mpro at low pHs. Moreover, we analysed the docking interactions of PF-00835231 from Pfizer in the preclinical phase, which shows excellent affinity with the Mpro at different pHs. (4) Conclusion: Overall, these findings indicate that SARS-CoV-2 Mpro is highly stable at acidic pH conditions, and this inhibitor could have a desirable function at this condition.
format	article
author	Haruna Luz Barazorda-Ccahuana Miroslava Nedyalkova Francesc Mas Sergio Madurga
author_facet	Haruna Luz Barazorda-Ccahuana Miroslava Nedyalkova Francesc Mas Sergio Madurga
author_sort	Haruna Luz Barazorda-Ccahuana
title	Unveiling the Effect of Low pH on the SARS-CoV-2 Main Protease by Molecular Dynamics Simulations
title_short	Unveiling the Effect of Low pH on the SARS-CoV-2 Main Protease by Molecular Dynamics Simulations
title_full	Unveiling the Effect of Low pH on the SARS-CoV-2 Main Protease by Molecular Dynamics Simulations
title_fullStr	Unveiling the Effect of Low pH on the SARS-CoV-2 Main Protease by Molecular Dynamics Simulations
title_full_unstemmed	Unveiling the Effect of Low pH on the SARS-CoV-2 Main Protease by Molecular Dynamics Simulations
title_sort	unveiling the effect of low ph on the sars-cov-2 main protease by molecular dynamics simulations
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/dbb96d94078d44d4b0c1278f7c43fb15
work_keys_str_mv	AT harunaluzbarazordaccahuana unveilingtheeffectoflowphonthesarscov2mainproteasebymoleculardynamicssimulations AT miroslavanedyalkova unveilingtheeffectoflowphonthesarscov2mainproteasebymoleculardynamicssimulations AT francescmas unveilingtheeffectoflowphonthesarscov2mainproteasebymoleculardynamicssimulations AT sergiomadurga unveilingtheeffectoflowphonthesarscov2mainproteasebymoleculardynamicssimulations
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Unveiling the Effect of Low pH on the SARS-CoV-2 Main Protease by Molecular Dynamics Simulations

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