Extended ensemble simulations of a SARS-CoV-2 nsp1-5'-UTR complex

PLoS Comput Biol. 2022 Jan 19;18(1):e1009804. doi: 10.1371/journal.pcbi.1009804. eCollection 2022 Jan.


Nonstructural protein 1 (nsp1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 180-residue protein that blocks translation of host mRNAs in SARS-CoV-2-infected cells. Although it is known that SARS-CoV-2's own RNA evades nsp1's host translation shutoff, the molecular mechanism underlying the evasion was poorly understood. We performed an extended ensemble molecular dynamics simulation to investigate the mechanism of the viral RNA evasion. Simulation results suggested that the stem loop structure of the SARS-CoV-2 RNA 5'-untranslated region (SL1) binds to both nsp1's N-terminal globular region and intrinsically disordered region. The consistency of the results was assessed by modeling nsp1-40S ribosome structure based on reported nsp1 experiments, including the X-ray crystallographic structure analysis, the cryo-EM electron density map, and cross-linking experiments. The SL1 binding region predicted from the simulation was open to the solvent, yet the ribosome could interact with SL1. Cluster analysis of the binding mode and detailed analysis of the binding poses suggest residues Arg124, Lys47, Arg43, and Asn126 may be involved in the SL1 recognition mechanism, consistent with the existing mutational analysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19 / virology*
  • Computational Biology
  • Host-Pathogen Interactions / genetics*
  • Humans
  • Models, Genetic
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Biosynthesis
  • SARS-CoV-2* / genetics
  • SARS-CoV-2* / pathogenicity
  • Untranslated Regions / genetics*
  • Viral Nonstructural Proteins* / chemistry
  • Viral Nonstructural Proteins* / genetics
  • Viral Nonstructural Proteins* / metabolism


  • NSP1 protein, SARS-CoV-2
  • Untranslated Regions
  • Viral Nonstructural Proteins

Grants and funding

SS was supported by a Grant-in-Aid for Early-Career Scientists from the Japan Society for the Promotion of Science (JSPS; https://www.jsps.go.jp/english/), Japan (JP16K17778), by Grants-in-Aid for Scientific Research (A) from the JSPS (JP16H02484 and JP21H04912), and by a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology (MEXT; https://www.mext.go.jp/en/; JP19H05410). KK was supported by a Grant-in-Aid for Scientific Research (C) from the JSPS (JP20K12069). JI was supported by a Grant-in-Aid for Scientific Research (C) from the JSPS (JP20K12041). HK was supported by by Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under Grant Number JP21am0101106, Agency for Medical Research and Development (AMED; https://www.amed.go.jp/en/), Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.