Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease
The main protease (M pro ) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of M pro , a cysteine protease, have been determined, facilitating structure-based drug design. M pro plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins. In addition to the catalytic dyad His41-Cys145, M pro contains multiple histidines including His163, His164, and His172. The protonation states of these histidines and the catalytic nu-cleophile Cys145 have been debated in previous studies of SARS-CoV M pro , but have yet to be investigated for SARS-CoV-2. In this work we have used molecular dynamics simulations to determine the structural stability of SARS-CoV-2 M pro as a function of the protonation assignments for these residues. We simulated both the apo and inhibitor-bound enzyme and found that the conformational stability of the binding site, bound inhibitors, and the hydrogen bond networks of M pro are highly sensitive to these assignments. Additionally, the two inhibitors studied, the peptidomimetic N3 and an α -ketoamide, display distinct His41/His164 protonation-state-dependent stabilities. While the apo and the N3-bound systems favored N δ (HD) and N ϵ (HE) protonation of His41 and His164, respectively, the α -ketoamide was not stably bound in this state. Our results illustrate the importance of using appropriate histidine protonation states to accurately model the structure and dynamics of SARS-CoV-2 M pro in both the apo and inhibitor-bound states, a necessary prerequisite for drug-design efforts.
Errataetall: |
UpdateIn: Chem Sci. 2020 Nov 26;12(4):1513-1527. - PMID 35356437 |
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Medienart: |
E-Artikel |
Erscheinungsjahr: |
2020 |
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Erschienen: |
2020 |
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Zur Gesamtaufnahme - year:2020 |
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Enthalten in: |
bioRxiv : the preprint server for biology - (2020) vom: 10. Sept. |
Sprache: |
Englisch |
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Beteiligte Personen: |
Pavlova, Anna [VerfasserIn] |
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Date Revised 01.04.2022 published: Electronic UpdateIn: Chem Sci. 2020 Nov 26;12(4):1513-1527. - PMID 35356437 Citation Status PubMed-not-MEDLINE |
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doi: |
10.1101/2020.09.07.286344 |
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PPN (Katalog-ID): |
NLM315069880 |
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520 | |a The main protease (M pro ) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of M pro , a cysteine protease, have been determined, facilitating structure-based drug design. M pro plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins. In addition to the catalytic dyad His41-Cys145, M pro contains multiple histidines including His163, His164, and His172. The protonation states of these histidines and the catalytic nu-cleophile Cys145 have been debated in previous studies of SARS-CoV M pro , but have yet to be investigated for SARS-CoV-2. In this work we have used molecular dynamics simulations to determine the structural stability of SARS-CoV-2 M pro as a function of the protonation assignments for these residues. We simulated both the apo and inhibitor-bound enzyme and found that the conformational stability of the binding site, bound inhibitors, and the hydrogen bond networks of M pro are highly sensitive to these assignments. Additionally, the two inhibitors studied, the peptidomimetic N3 and an α -ketoamide, display distinct His41/His164 protonation-state-dependent stabilities. While the apo and the N3-bound systems favored N δ (HD) and N ϵ (HE) protonation of His41 and His164, respectively, the α -ketoamide was not stably bound in this state. Our results illustrate the importance of using appropriate histidine protonation states to accurately model the structure and dynamics of SARS-CoV-2 M pro in both the apo and inhibitor-bound states, a necessary prerequisite for drug-design efforts | ||
650 | 4 | |a Preprint | |
700 | 1 | |a Lynch, Diane L |e verfasserin |4 aut | |
700 | 1 | |a Daidone, Isabella |e verfasserin |4 aut | |
700 | 1 | |a Zanetti-Polzi, Laura |e verfasserin |4 aut | |
700 | 1 | |a Smith, Micholas Dean |e verfasserin |4 aut | |
700 | 1 | |a Chipot, Chris |e verfasserin |4 aut | |
700 | 1 | |a Kneller, Daniel W |e verfasserin |4 aut | |
700 | 1 | |a Kovalevsky, Andrey |e verfasserin |4 aut | |
700 | 1 | |a Coates, Leighton |e verfasserin |4 aut | |
700 | 1 | |a Golosov, Andrei A |e verfasserin |4 aut | |
700 | 1 | |a Dickson, Callum J |e verfasserin |4 aut | |
700 | 1 | |a Velez-Vega, Camilo |e verfasserin |4 aut | |
700 | 1 | |a Duca, José S |e verfasserin |4 aut | |
700 | 1 | |a Vermaas, Josh V |e verfasserin |4 aut | |
700 | 1 | |a Pang, Yui Tik |e verfasserin |4 aut | |
700 | 1 | |a Acharya, Atanu |e verfasserin |4 aut | |
700 | 1 | |a Parks, Jerry M |e verfasserin |4 aut | |
700 | 1 | |a Smith, Jeremy C |e verfasserin |4 aut | |
700 | 1 | |a Gumbart, James C |e verfasserin |4 aut | |
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