ORF3b is one of the SARS-CoV-2 accessory proteins. Previous experimental study suggested that ORF3b prevents IRF3 translocating to nucleus. However, the biophysical mechanism of ORF3b-IRF3 interaction is elusive. Here, we explored the conformation ensemble of ORF3b using all-atom replica exchange molecular dynamics simulation. Disordered ORF3b has mixed α-helix, β-turn and loop conformers. The potential ORF3b-IRF3 binding modes were searched by docking representative ORF3b conformers with IRF3, and 50 ORF3b-IRF3 complex poses were screened using molecular dynamics simulations ranging from 500 to 1000 ns. We found that ORF3b binds IRF3 predominantly on its CBP binding and phosphorylated pLxIS motifs, with CBP binding site has the highest binding affinity. The ORF3b-IRF3 binding residues are highly conserved in SARS-CoV-2. Our results provided biophysics insights into ORF3b-IRF3 interaction and explained its interferon antagonism mechanism.
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