TY - JOUR
T1 - Multiple protonation states in ligand-free SARS-CoV-2 main protease revealed by large-scale quantum molecular dynamics simulations
AU - Ono, Junichi
AU - Koshimizu, Uika
AU - Fukunishi, Yoshifumi
AU - Nakai, Hiromi
N1 - Funding Information:
This work was supported in part by a Grant-in-Aid for Scientific Research (S) “KAKENHI Grant Number JP18H05264” and Grant-in-Aid for Scientific Research on Innovative Areas “KAKENHI Grant Number JP20H05447” from the Japan Society for the Promotion of Science (JSPS) and the Project Focused on Developing Key Technology for Discovering and Manufacturing Drugs for Next-Generation Treatment and Diagnosis from Japan Agency for Medical Research and Development (AMED). The calculations were performed using the Fugaku computer provided by the RIKEN Advanced Institute for Computational Science, Flow provided by the Information Technology Center, Nagoya University, and Oakforest-PACS provided by the Information Technology Center, The University of Tokyo, through the HPCI System Research project (Project ID: hp200116 and hp210214), and at the Research Center for Computational Science (RCCS), Okazaki Research Facilities, National Institutes of Natural Sciences (NIIS), Japan.
Publisher Copyright:
© 2022 Elsevier B.V.
PY - 2022/5
Y1 - 2022/5
N2 - 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.
AB - 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.
KW - Main protease
KW - Proton transfer
KW - Quantum molecular dynamics
KW - SARS-CoV-2
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U2 - 10.1016/j.cplett.2022.139489
DO - 10.1016/j.cplett.2022.139489
M3 - Article
AN - SCOPUS:85125467581
SN - 0009-2614
VL - 794
JO - Chemical Physics Letters
JF - Chemical Physics Letters
M1 - 139489
ER -