Multiple protonation states in ligand-free SARS-CoV-2 main protease revealed by large-scale quantum molecular dynamics simulations

Junichi Ono, Uika Koshimizu, Yoshifumi Fukunishi, Hiromi Nakai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The main protease (Mpro) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) catalyzes the cleavage of polyproteins for viral replication. Here, large-scale quantum molecular dynamics and metadynamics simulations for ligand-free Mpro were performed, where all the atoms were treated quantum-mechanically, focusing on elucidation of the controversial active-site protonation state. The simulations clarified that the interconverting multiple protonation states exist in unliganded Mpro, and the catalytically relevant ion-pair state is more stable than the neutral state, which is consistent with neutron crystallography. The results highlight the importance of the ion-pair state for repurposing or discovering antiviral drugs that target Mpro.

Original languageEnglish
Article number139489
JournalChemical Physics Letters
Volume794
DOIs
Publication statusPublished - 2022 May
Externally publishedYes

Keywords

  • Main protease
  • Proton transfer
  • Quantum molecular dynamics
  • SARS-CoV-2

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Physical and Theoretical Chemistry

Fingerprint

Dive into the research topics of 'Multiple protonation states in ligand-free SARS-CoV-2 main protease revealed by large-scale quantum molecular dynamics simulations'. Together they form a unique fingerprint.

Cite this