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EnglishThe 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.
| Titolo: | Tuning proton transfer thermodynamics in SARS-CoV-2 main protease: Implications for catalysis and inhibitor design | |
| Autori: | DAIDONE, ISABELLA (Corresponding) | |
| Data di pubblicazione: | 2021 | |
| Rivista: | ||
| Handle: | http://hdl.handle.net/11697/177756 | |
| Appare nelle tipologie: | 1.1 Articolo in rivista |
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