Tuning Proton Transfer Thermodynamics in SARS-CoV-2 Main Protease : Implications for Catalysis and Inhibitor Design
The catalytic reaction in SARS-CoV-2 main protease is activated by a proton transfer (PT) from Cys145 to His41. The same PT is likely also required for the covalent binding of some inhibitors. Here we use a multiscale computational approach to investigate the PT thermodynamics in the apo enzyme and in complex with two potent inhibitors, N3 and the α-ketoamide 13b. We show that with the inhibitors the free energy cost to reach the charge-separated state of the active-site dyad is lower, with N3 inducing the most significant reduction. We also show that a few key sites (including specific water molecules) significantly enhance or reduce the thermodynamic feasibility of the PT reaction, with selective desolvation of the active site playing a crucial role. The approach presented is a cost-effective procedure to identify the enzyme regions that control the activation of the catalytic reaction and is thus also useful to guide the design of inhibitors.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
The journal of physical chemistry letters - 12(2021), 17 vom: 06. Mai, Seite 4195-4202 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zanetti-Polzi, Laura [VerfasserIn] |
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| Links: |
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| Themen: |
Antiviral Agents |
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| Anmerkungen: |
Date Completed 12.05.2021 Date Revised 16.02.2024 published: Print-Electronic UpdateOf: ChemRxiv. 2020 Nov 06;:. - PMID 33200115 Citation Status MEDLINE |
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| doi: |
10.1021/acs.jpclett.1c00425 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM324535996 |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a UpdateOf: ChemRxiv. 2020 Nov 06;:. - PMID 33200115 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The catalytic reaction in SARS-CoV-2 main protease is activated by a proton transfer (PT) from Cys145 to His41. The same PT is likely also required for the covalent binding of some inhibitors. Here we use a multiscale computational approach to investigate the PT thermodynamics in the apo enzyme and in complex with two potent inhibitors, N3 and the α-ketoamide 13b. We show that with the inhibitors the free energy cost to reach the charge-separated state of the active-site dyad is lower, with N3 inducing the most significant reduction. We also show that a few key sites (including specific water molecules) significantly enhance or reduce the thermodynamic feasibility of the PT reaction, with selective desolvation of the active site playing a crucial role. The approach presented is a cost-effective procedure to identify the enzyme regions that control the activation of the catalytic reaction and is thus also useful to guide the design of inhibitors | ||
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| 650 | 7 | |a Protease Inhibitors |2 NLM | |
| 650 | 7 | |a Protons |2 NLM | |
| 650 | 7 | |a Viral Matrix Proteins |2 NLM | |
| 650 | 7 | |a membrane protein, SARS-CoV-2 |2 NLM | |
| 700 | 1 | |a Smith, Micholas Dean |e verfasserin |4 aut | |
| 700 | 1 | |a Chipot, Chris |e verfasserin |4 aut | |
| 700 | 1 | |a Gumbart, James C |e verfasserin |4 aut | |
| 700 | 1 | |a Lynch, Diane L |e verfasserin |4 aut | |
| 700 | 1 | |a Pavlova, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Jeremy C |e verfasserin |4 aut | |
| 700 | 1 | |a Daidone, Isabella |e verfasserin |4 aut | |
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