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

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.

Automated summary

This study utilizes molecular dynamics simulations to construct a Markov state model and investigate the translocation dynamics of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). The research reveals the key steps of translocation and the asynchronous movement of the template-primer duplex, providing new insights into viral replication and transcription.