Tuning Proton Transfer Thermodynamics in SARS-CoV-2 Main Protease: Implications for Catalysis and Inhibitor Design

Laura Zanetti-Polzi, Micholas Dean Smith, Chris Chipot, James C Gumbart, Diane L Lynch, Anna Pavlova, Jeremy C Smith, Isabella Daidone

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4195-4202
Number of pages8
JournalThe journal of physical chemistry letters
Volume12
Issue number17
Early online dateApr 26 2021
DOIs
StatePublished - May 6 2021

Keywords

  • COVID-19
  • severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
  • Novel coronavirus
  • Coronavirus
  • 2019-nCoV
  • Pandemic

ASJC Scopus subject areas

  • Materials Science(all)
  • Physical and Theoretical Chemistry

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