SARS-CoV-2 RNA-Dependent RNA Polymerase Follows Asynchronous Translocation Pathway for Viral Transcription and Replication

Xiaowei Wang, Tiantian Xu, Yuan Yao, Peter Pak Hang Cheung, Xin Gao, Lu Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Translocation is one essential step for the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) to exert viral replication and transcription. Although cryo-EM structures of SARS-CoV-2 RdRp are available, the molecular mechanisms of dynamic translocation remain elusive. Herein, we constructed a Markov state model based on extensive molecular dynamics simulations to elucidate the translocation dynamics of the SARS-CoV-2 RdRp. We identified two intermediates that pinpoint the rate-limiting step of translocation and characterize the asynchronous movement of the template-primer duplex. The 3′-terminal nucleotide in the primer strand lags behind due to the uneven distribution of protein-RNA interactions, while the translocation of the template strand is delayed by the hurdle residue K500. Even so, the two strands share the same “ratchet” to stabilize the polymerase in the post-translocation state, suggesting a Brownian-ratchet model. Overall, our study provides intriguing insights into SARS-CoV-2 replication and transcription, which would open a new avenue for drug discoveries.

Original languageEnglish (US)
Pages (from-to)10119-10128
Number of pages10
JournalJournal of Physical Chemistry Letters
Volume14
Issue number45
DOIs
StatePublished - Nov 16 2023

Bibliographical note

Publisher Copyright:
© 2023 American Chemical Society.

ASJC Scopus subject areas

  • General Materials Science
  • Physical and Theoretical Chemistry

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